19-18870253-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001492.6(GDF1):ā€‹c.55C>Gā€‹(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: š‘“ 0.0011 ( 3 hom., cov: 32)
Exomes š‘“: 0.00013 ( 1 hom. )

Consequence

GDF1
NM_001492.6 missense

Scores

1
1
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.758
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]
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]

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ACMG classification

Classification made for transcript

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
GDF1NM_001492.6 linkuse as main transcriptc.55C>G p.Leu19Val missense_variant 7/8 ENST00000247005.8 NP_001483.3
CERS1NM_021267.5 linkuse as main transcriptc.*324C>G 3_prime_UTR_variant 7/8 ENST00000623882.4 NP_067090.1
GDF1NM_001387438.1 linkuse as main transcriptc.55C>G p.Leu19Val missense_variant 4/5 NP_001374367.1
CERS1NM_001387440.1 linkuse as main transcriptc.*324C>G 3_prime_UTR_variant 7/7 NP_001374369.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GDF1ENST00000247005.8 linkuse as main transcriptc.55C>G p.Leu19Val missense_variant 7/81 NM_001492.6 ENSP00000247005 P1
CERS1ENST00000623882.4 linkuse as main transcriptc.*324C>G 3_prime_UTR_variant 7/81 NM_021267.5 ENSP00000485308 P2P27544-1

Frequencies

GnomAD3 genomes
AF:
0.00114
AC:
172
AN:
150676
Hom.:
3
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:3
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 04, 2016- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 25, 2023- -
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs370986101; hg19: chr19-18981062; API