19-18868694-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_001492.6(GDF1):​c.1022G>A​(p.Arg341His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000449 in 1,557,398 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

GDF1
NM_001492.6 missense

Scores

4
7
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.06
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 Uncertain_significance. Variant got 2 ACMG points.

PM1
In a chain Embryonic growth/differentiation factor 1 (size 118) in uniprot entity GDF1_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_001492.6

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GDF1NM_001492.6 linkc.1022G>A p.Arg341His missense_variant Exon 8 of 8 ENST00000247005.8 NP_001483.3 P27539A0A024R7N8
CERS1NM_021267.5 linkc.*1291G>A 3_prime_UTR_variant Exon 8 of 8 ENST00000623882.4 NP_067090.1 P27544-1
GDF1NM_001387438.1 linkc.1022G>A p.Arg341His missense_variant Exon 5 of 5 NP_001374367.1
CERS1NM_001387440.1 linkc.*1883G>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
GDF1ENST00000247005.8 linkc.1022G>A p.Arg341His missense_variant Exon 8 of 8 1 NM_001492.6 ENSP00000247005.5 P27539
CERS1ENST00000623882 linkc.*1291G>A 3_prime_UTR_variant Exon 8 of 8 1 NM_021267.5 ENSP00000485308.1 P27544-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151916
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000427
AC:
6
AN:
1405482
Hom.:
0
Cov.:
31
AF XY:
0.00000288
AC XY:
2
AN XY:
694350
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000270
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000462
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151916
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74224
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
0.0020
T
BayesDel_noAF
Benign
-0.23
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.80
D;.
Eigen
Benign
-0.019
Eigen_PC
Benign
-0.086
FATHMM_MKL
Benign
0.23
N
LIST_S2
Pathogenic
0.99
D;.
M_CAP
Pathogenic
0.70
D
MetaRNN
Uncertain
0.54
D;D
MetaSVM
Uncertain
0.40
D
MutationAssessor
Uncertain
2.1
M;.
PROVEAN
Uncertain
-3.3
D;.
REVEL
Uncertain
0.48
Sift
Uncertain
0.0040
D;.
Sift4G
Uncertain
0.0080
D;D
Vest4
0.33
MVP
0.45
MPC
2.3
ClinPred
0.96
D
GERP RS
2.4
Varity_R
0.19
gMVP
0.76

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: rs1446194780; hg19: chr19-18979503; API