chr19-18868625-A-G

Position:

chr19-18868625-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM1PM5PP3PP5_Very_StrongBP4

The NM_001492.6(GDF1):c.1091T>C(p.Met364Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000209 in 1,571,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M364I) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

GDF1
NM_001492.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.14

Variant links:

Genes affected

GDF1 (HGNC:4214): (growth differentiation factor 1) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. Studies in rodents suggest that this protein is involved in the establishment of left-right asymmetry in early embryogenesis and in neural development in later embryogenesis. The encoded protein is translated from a bicistronic mRNA that also encodes ceramide synthase 1. Mutations in this gene are associated with several congenital cardiovascular malformations. [provided by RefSeq, Jul 2016]

GDF1 links:

CERS1 (HGNC:14253): (ceramide synthase 1) This gene encodes a ceramide synthase enzyme, which catalyzes the synthesis of ceramide, the hydrophobic moiety of sphingolipids. The encoded enzyme synthesizes 18-carbon (C18) ceramide in brain neurons. Elevated expression of this gene may be associated with increased longevity, while decreased expression of this gene may be associated with myoclonus epilepsy with dementia in human patients. This protein is transcribed from a monocistronic mRNA as well as a bicistronic mRNA, which also encodes growth differentiation factor 1. [provided by RefSeq, Jul 2016]

CERS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a chain Embryonic growth/differentiation factor 1 (size 118) in uniprot entity GDF1_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_001492.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-18868624-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1507891.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, Cadd, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 19-18868625-A-G is Pathogenic according to our data. Variant chr19-18868625-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.0835813). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GDF1	NM_001492.6 linkuse as main transcript	c.1091T>C	p.Met364Thr	missense_variant	8/8	ENST00000247005.8
CERS1	NM_021267.5 linkuse as main transcript	c.*1360T>C		3_prime_UTR_variant	8/8	ENST00000623882.4
GDF1	NM_001387438.1 linkuse as main transcript	c.1091T>C	p.Met364Thr	missense_variant	5/5
CERS1	NM_001387440.1 linkuse as main transcript	c.*1952T>C		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF1	ENST00000247005.8 linkuse as main transcript	c.1091T>C	p.Met364Thr	missense_variant	8/8	1	NM_001492.6	P1
CERS1	ENST00000623882.4 linkuse as main transcript	c.*1360T>C		3_prime_UTR_variant	8/8	1	NM_021267.5	P2	P27544-1

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000508

AC:

AN:

182990

Hom.:

AF XY:

0.000526

AC XY:

AN XY:

98798

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000708

Gnomad ASJ exome

AF:

0.00889

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.00104

GnomAD4 exome

AF:

0.000202

AC:

287

AN:

1419596

Hom.:

Cov.:

AF XY:

0.000212

AC XY:

149

AN XY:

702218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000512

Gnomad4 ASJ exome

AF:

0.00771

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000367

Gnomad4 OTH exome

AF:

0.000852

GnomAD4 genome

AF:

0.000276

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.000310

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000998

Hom.:

Bravo

AF:

0.000306

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000360

AC:

ExAC

AF:

0.000213

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 08, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GDF1 protein function. ClinVar contains an entry for this variant (Variation ID: 522571). This missense change has been observed in individual(s) with congenital heart disease and/or abnormality of the cardiovascular system (PMID: 26633542, 28991257, 34958143). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 28991257). This variant is present in population databases (rs374016704, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 364 of the GDF1 protein (p.Met364Thr). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31876989, 31818857, 26633542, 28991257, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2020	- -

Heart, malformation of

Pathogenic:1

Likely pathogenic, no assertion criteria provided

curation

Reproductive Health Research and Development, BGI Genomics

Jan 06, 2020

NM_001492.4:c.1091T>C in the GDF1 gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been reported to be a common cause of congenital heart disease in the Ashkenazi Jewish population and has been found in homozygosity in 10 affected individuals (PMID: 28991257). Additional evidence supports homozygosity for p.Met364Thr in CHD risk among Ashkenazim. p.Met364Thr shows remarkable violation of Hardy Weinberg equilibrium among Ashkenazi CHD cases, (P = 5.5x10-38, 1-df chi-square test with Yates correction). In contrast, among 302 Ashkenazi autism parental controls and 926 additional Ashkenazi adults from an independent cohort without CHD, there were no homozygotes and 12 heterozygotes (two-sided Fisher's Exact P = 2.8x10-9). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, MutationTaster, REVEL and SIFTT. We interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PM3. -

Congenital heart defects, multiple types, 6

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.087

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;.

M_CAP

Pathogenic

0.86

MetaRNN

Benign

0.084

T;T

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

3.3

M;.

MutationTaster

Benign

1.0

D;D

PROVEAN

Pathogenic

-5.6

D;.

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Vest4

0.82

MVP

0.71

MPC

2.2

ClinPred

0.19

GERP RS

3.8

Varity_R

0.90

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over