chr19-18868896-C-T

Variant names:

• chr19-18868896-C-T
• rs1349040611
• NM_001492.6:c.820G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP3

The NM_001492.6(GDF1):​c.820G>A​(p.Val274Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000849 in 1,412,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: GDF1 NM_001492.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.530

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]

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a disulfide_bond (size 70) in uniprot entity GDF1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001492.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF1	NM_001492.6	c.820G>A	p.Val274Met	missense_variant	Exon 8 of 8	ENST00000247005.8	NP_001483.3
CERS1	NM_021267.5	c.*1089G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000623882.4	NP_067090.1
GDF1	NM_001387438.1	c.820G>A	p.Val274Met	missense_variant	Exon 5 of 5		NP_001374367.1
CERS1	NM_001387440.1	c.*1681G>A		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	c.820G>A	p.Val274Met	missense_variant	Exon 8 of 8	1	NM_001492.6	ENSP00000247005.5
CERS1	ENST00000623882	c.*1089G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_021267.5	ENSP00000485308.1

Frequencies

GnomAD3 genomes AF: 0.0000203 AC: 3 AN: 148122 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000301

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000712 AC: 9 AN: 1264594 Hom.: 0 Cov.: 31 AF XY: 0.00000801 AC XY: 5 AN XY: 624332

African (AFR) AF: 0.0000409 AC: 1 AN: 24442

American (AMR) AF: 0.0000348 AC: 1 AN: 28732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20210

East Asian (EAS) AF: 0.00 AC: 0 AN: 23110

South Asian (SAS) AF: 0.00 AC: 0 AN: 74578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3686

European-Non Finnish (NFE) AF: 0.00000595 AC: 6 AN: 1008920

Other (OTH) AF: 0.0000200 AC: 1 AN: 49920

GnomAD4 genome AF: 0.0000203 AC: 3 AN: 148122 Hom.: 0 Cov.: 33 AF XY: 0.0000277 AC XY: 2 AN XY: 72144

African (AFR) AF: 0.0000244 AC: 1 AN: 41060

American (AMR) AF: 0.00 AC: 0 AN: 14922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000301 AC: 2 AN: 66444

Other (OTH) AF: 0.00 AC: 0 AN: 2038

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.91	D;.
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	2.9	M;.
PROVEAN	Benign	-2.3	N;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0050	D;D
Vest4		0.47
MutPred		0.68		Gain of MoRF binding (P = 0.1059);Gain of MoRF binding (P = 0.1059);
MVP		0.63
MPC		2.1
ClinPred		0.99	D
GERP RS		2.2
Varity_R		0.23
gMVP		0.39
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1349040611; hg19: chr19-18979705;