rs181918871

Positions:

• chr19-18869328-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001492.6(GDF1):​c.388G>A​(p.Val130Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000851 in 1,528,002 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (7 hom.)
• Consequence: GDF1 NM_001492.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.298

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

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001492.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0046730638).
• BP6: Variant 19-18869328-C-T is Benign according to our data. Variant chr19-18869328-C-T is described in ClinVar as [Benign]. Clinvar id is 258161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18869328-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000451 (620/1376128) while in subpopulation AFR AF= 0.0169 (512/30382). AF 95% confidence interval is 0.0156. There are 7 homozygotes in gnomad4_exome. There are 275 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF1	NM_001492.6	c.388G>A	p.Val130Ile	missense_variant	8/8	ENST00000247005.8
CERS1	NM_021267.5	c.*657G>A		3_prime_UTR_variant	8/8	ENST00000623882.4
GDF1	NM_001387438.1	c.388G>A	p.Val130Ile	missense_variant	5/5
CERS1	NM_001387440.1	c.*1249G>A		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF1	ENST00000247005.8	c.388G>A	p.Val130Ile	missense_variant	8/8	1	NM_001492.6	P1
CERS1	ENST00000623882.4	c.*657G>A		3_prime_UTR_variant	8/8	1	NM_021267.5	P2

Frequencies

GnomAD3 genomes AF: 0.00445 AC: 676 AN: 151768 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000590

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.000782 AC: 97 AN: 124118 Hom.: 2 AF XY: 0.000746 AC XY: 51 AN XY: 68402

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.000701

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000898

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000434

Gnomad OTH exome AF: 0.000261

GnomAD4 exome AF: 0.000451 AC: 620 AN: 1376128 Hom.: 7 Cov.: 31 AF XY: 0.000405 AC XY: 275 AN XY: 679352

Gnomad4 AFR exome AF: 0.0169

Gnomad4 AMR exome AF: 0.000676

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000253

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000176

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00448 AC: 681 AN: 151874 Hom.: 3 Cov.: 33 AF XY: 0.00443 AC XY: 329 AN XY: 74226

Gnomad4 AFR AF: 0.0157

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000590

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00312 Hom.: 0

Bravo AF: 0.00528

ESP6500AA AF: 0.0100 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000367 AC: 32

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.33	T;.
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	0.43	N;.
REVEL	Benign	0.038
Sift	Benign	0.16	T;.
Sift4G	Uncertain	0.051	T;T
Vest4		0.030
MVP		0.12
MPC		0.77
ClinPred		0.0023	T
GERP RS		0.90
Varity_R		0.033
gMVP		0.082

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

Other links and lift over

dbSNP: rs181918871; hg19: chr19-18980137;