dbSNP rs1446194780: GDF1:p.Arg341Leu (chr19-18868694-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_001492.6(GDF1):c.1022G>T(p.Arg341Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,405,482 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R341H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GDF1
NM_001492.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.06

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 Uncertain_significance. Variant got 4 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

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF1	NM_001492.6 link	c.1022G>T	p.Arg341Leu	missense_variant	Exon 8 of 8	ENST00000247005.8	NP_001483.3	P27539A0A024R7N8
CERS1	NM_021267.5 link	c.*1291G>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000623882.4	NP_067090.1	P27544-1
GDF1	NM_001387438.1 link	c.1022G>T	p.Arg341Leu	missense_variant	Exon 5 of 5		NP_001374367.1
CERS1	NM_001387440.1 link	c.*1883G>T		3_prime_UTR_variant	Exon 7 of 7		NP_001374369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF1	ENST00000247005.8 link	c.1022G>T	p.Arg341Leu	missense_variant	Exon 8 of 8	1	NM_001492.6	ENSP00000247005.5		P27539
CERS1	ENST00000623882 link	c.*1291G>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_021267.5	ENSP00000485308.1		P27544-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000213

AC:

AN:

1405482

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

694350

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000270

Gnomad4 ASJ exome

AF:

0.0000399

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000125

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000333

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;.

Eigen

Benign

0.018

Eigen_PC

Benign

-0.062

FATHMM_MKL

Benign

0.45

LIST_S2

Pathogenic

0.98

D;.

M_CAP

Pathogenic

0.81

MetaRNN

Uncertain

0.64

D;D

MetaSVM

Uncertain

0.42

MutationAssessor

Uncertain

2.5

M;.

PROVEAN

Pathogenic

-4.5

D;.

REVEL

Uncertain

0.61

Sift

Uncertain

0.0050

D;.

Sift4G

Uncertain

0.010

D;D

Vest4

0.49

MVP

0.34

MPC

2.3

ClinPred

0.98

GERP RS

2.4

Varity_R

0.32

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over