chr19-18870253-G-C

Position:

• chr19-18870253-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001492.6(GDF1):​c.55C>G​(p.Leu19Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,551,400 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: GDF1 NM_001492.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.758

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013957262).
• BP6: Variant 19-18870253-G-C is Benign according to our data. Variant chr19-18870253-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258162.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}. Variant chr19-18870253-G-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF1	NM_001492.6	c.55C>G	p.Leu19Val	missense_variant	7/8	ENST00000247005.8	NP_001483.3
CERS1	NM_021267.5	c.*324C>G		3_prime_UTR_variant	7/8	ENST00000623882.4	NP_067090.1
GDF1	NM_001387438.1	c.55C>G	p.Leu19Val	missense_variant	4/5		NP_001374367.1
CERS1	NM_001387440.1	c.*324C>G		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	c.55C>G	p.Leu19Val	missense_variant	7/8	1	NM_001492.6	ENSP00000247005	P1
CERS1	ENST00000623882.4	c.*324C>G		3_prime_UTR_variant	7/8	1	NM_021267.5	ENSP00000485308	P2

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 172 AN: 150676 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00401

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000396

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00333

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000297 AC: 44 AN: 147950 Hom.: 0 AF XY: 0.000210 AC XY: 17 AN XY: 80780

Gnomad AFR exome AF: 0.00385

Gnomad AMR exome AF: 0.000526

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000433

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.000235

GnomAD4 exome AF: 0.000129 AC: 180 AN: 1400598 Hom.: 1 Cov.: 33 AF XY: 0.000111 AC XY: 77 AN XY: 691832

Gnomad4 AFR exome AF: 0.00402

Gnomad4 AMR exome AF: 0.000557

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000554

Gnomad4 OTH exome AF: 0.000361

GnomAD4 genome AF: 0.00114 AC: 172 AN: 150802 Hom.: 3 Cov.: 32 AF XY: 0.00111 AC XY: 82 AN XY: 73678

Gnomad4 AFR AF: 0.00400

Gnomad4 AMR AF: 0.000396

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000141 Hom.: 0

Bravo AF: 0.00136

ESP6500AA AF: 0.00122 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000180 AC: 19

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 04, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 25, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	1.2
DANN	Benign	0.69
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.35	T;.
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	-0.39	N;.
REVEL	Benign	0.16
Sift	Benign	0.22	T;.
Sift4G	Uncertain	0.054	T;T
Vest4		0.13
MVP		0.13
MPC		0.95
ClinPred		0.0057	T
GERP RS		-1.1
Varity_R		0.041
gMVP		0.30

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: rs370986101; hg19: chr19-18981062;