chr19-18869245-T-TGCC

Position:

chr19-18869245-T-TGCC

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBA1

The NM_001492.6(GDF1):c.468_470dupGGC(p.Ala157dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0489 in 1,427,884 control chromosomes in the GnomAD database, including 1,635 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 170 hom., cov: 32)

Exomes 𝑓: 0.050 ( 1465 hom. )

Consequence

GDF1
NM_001492.6 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.179

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 Benign. Variant got -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001492.6

BP6

Variant 19-18869245-T-TGCC is Benign according to our data. Variant chr19-18869245-T-TGCC is described in ClinVar as [Benign]. Clinvar id is 215496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF1	NM_001492.6 linkuse as main transcript	c.468_470dupGGC	p.Ala157dup	disruptive_inframe_insertion	8/8	ENST00000247005.8	NP_001483.3	P27539A0A024R7N8
CERS1	NM_021267.5 linkuse as main transcript	c.737_739dupGGC		3_prime_UTR_variant	8/8	ENST00000623882.4	NP_067090.1	P27544-1
GDF1	NM_001387438.1 linkuse as main transcript	c.468_470dupGGC	p.Ala157dup	disruptive_inframe_insertion	5/5		NP_001374367.1
CERS1	NM_001387440.1 linkuse as main transcript	c.1329_1331dupGGC		3_prime_UTR_variant	7/7		NP_001374369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF1	ENST00000247005.8 linkuse as main transcript	c.468_470dupGGC	p.Ala157dup	disruptive_inframe_insertion	8/8	1	NM_001492.6	ENSP00000247005.5		P27539
CERS1	ENST00000623882 linkuse as main transcript	c.737_739dupGGC		3_prime_UTR_variant	8/8	1	NM_021267.5	ENSP00000485308.1		P27544-1

Frequencies

GnomAD3 genomes

AF:

0.0425

AC:

6391

AN:

150494

Hom.:

169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0155

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.0392

Gnomad ASJ

AF:

0.0596

Gnomad EAS

AF:

0.0998

Gnomad SAS

AF:

0.00869

Gnomad FIN

AF:

0.0659

Gnomad MID

AF:

0.0764

Gnomad NFE

AF:

0.0515

Gnomad OTH

AF:

0.0620

GnomAD3 exomes

AF:

0.0383

AC:

1196

AN:

31234

Hom.:

AF XY:

0.0372

AC XY:

688

AN XY:

18480

show subpopulations

Gnomad AFR exome

AF:

0.0226

Gnomad AMR exome

AF:

0.0251

Gnomad ASJ exome

AF:

0.0566

Gnomad EAS exome

AF:

0.0789

Gnomad SAS exome

AF:

0.00682

Gnomad FIN exome

AF:

0.0654

Gnomad NFE exome

AF:

0.0505

Gnomad OTH exome

AF:

0.0403

GnomAD4 exome

AF:

0.0496

AC:

63364

AN:

1277286

Hom.:

1465

Cov.:

AF XY:

0.0492

AC XY:

30869

AN XY:

627722

show subpopulations

Gnomad4 AFR exome

AF:

0.0139

Gnomad4 AMR exome

AF:

0.0266

Gnomad4 ASJ exome

AF:

0.0571

Gnomad4 EAS exome

AF:

0.0696

Gnomad4 SAS exome

AF:

0.00876

Gnomad4 FIN exome

AF:

0.0612

Gnomad4 NFE exome

AF:

0.0525

Gnomad4 OTH exome

AF:

0.0479

GnomAD4 genome

AF:

0.0424

AC:

6390

AN:

150598

Hom.:

170

Cov.:

AF XY:

0.0438

AC XY:

3225

AN XY:

73606

show subpopulations

Gnomad4 AFR

AF:

0.0155

Gnomad4 AMR

AF:

0.0392

Gnomad4 ASJ

AF:

0.0596

Gnomad4 EAS

AF:

0.0997

Gnomad4 SAS

AF:

0.00849

Gnomad4 FIN

AF:

0.0659

Gnomad4 NFE

AF:

0.0516

Gnomad4 OTH

AF:

0.0614

Bravo

AF:

0.0420

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 24, 2024	Variant summary: GDF1 c.468_470dupGGC (p.Ala158dup) results in an in-frame duplication that is predicted to duplicate one amino acid in the encoded protein. The variant allele was found at a frequency of 0.038 in 31234 control chromosomes in the gnomAD database, including 25 homozygotes. The observed variant frequency is approximately 30000-fold of the estimated maximal expected allele frequency for a pathogenic variant in GDF1 causing Congenital Heart Disease phenotype (1.3e-06). c.468_470dupGGC has been reported in the literature in individuals affected with Congenital Heart Disease (e.g. Meng_2017), however these report(s) do not provide unequivocal conclusions about association of the variant with Congenital Heart Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 215496). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Visceral heterotaxy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 11, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 31180159, 28973083) -

Progressive myoclonic epilepsy type 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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