rs944730356

Variant names:

• chr19-18869312-G-A
• rs944730356
• NM_001492.6:c.404C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-18869312-G-A
• chr19-18869312-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001492.6(GDF1):​c.404C>T​(p.Ala135Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 1,521,974 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000030 (1 hom.)
• Consequence: GDF1 NM_001492.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.561
• Publications: 1 publications found

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]

CERS1 Gene-Disease associations (from GenCC):

• progressive myoclonic epilepsy type 8

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044920802).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001492.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF1	NM_001492.6	MANE Select	c.404C>T	p.Ala135Val	missense	Exon 8 of 8	NP_001483.3
	CERS1	NM_021267.5	MANE Select	c.*673C>T		3_prime_UTR	Exon 8 of 8	NP_067090.1
	GDF1	NM_001387438.1		c.404C>T	p.Ala135Val	missense	Exon 5 of 5	NP_001374367.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF1	ENST00000247005.8	TSL:1 MANE Select	c.404C>T	p.Ala135Val	missense	Exon 8 of 8	ENSP00000247005.5
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.*673C>T		3_prime_UTR	Exon 8 of 8	ENSP00000485308.1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151792 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

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: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000306 AC: 36 AN: 117626 AF XY: 0.000276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00138

GnomAD4 exome AF: 0.0000299 AC: 41 AN: 1370182 Hom.: 1 Cov.: 31 AF XY: 0.0000340 AC XY: 23 AN XY: 676432

African (AFR) AF: 0.00 AC: 0 AN: 29410

American (AMR) AF: 0.00106 AC: 37 AN: 35012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24588

East Asian (EAS) AF: 0.00 AC: 0 AN: 33602

South Asian (SAS) AF: 0.00 AC: 0 AN: 78636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4038

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074356

Other (OTH) AF: 0.0000700 AC: 4 AN: 57178

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151792 Hom.: 0 Cov.: 33 AF XY: 0.0000405 AC XY: 3 AN XY: 74132

African (AFR) AF: 0.0000241 AC: 1 AN: 41418

American (AMR) AF: 0.000328 AC: 5 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67778

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000117

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.60	N
PhyloP100		0.56
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.030
Sift	Benign	0.51	T
Sift4G	Benign	1.0	T
Vest4		0.032
MutPred		0.25		Loss of disorder (P = 0.085)
MVP		0.14
MPC		1.5
ClinPred		0.031	T
GERP RS		-0.88
Varity_R		0.033
gMVP		0.14
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs944730356; hg19: chr19-18980121;