rs1554571225

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001001557.4(GDF6):​c.1287C>A​(p.Ser429Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

GDF6
NM_001001557.4 missense

Scores

3
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 3.58
Variant links:
Genes affected
GDF6 (HGNC:4221): (growth differentiation factor 6) 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. This protein is required for normal formation of some bones and joints in the limbs, skull, and axial skeleton. Mutations in this gene are associated with Klippel-Feil syndrome, microphthalmia, and Leber congenital amaurosis. [provided by RefSeq, Sep 2016]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GDF6NM_001001557.4 linkuse as main transcriptc.1287C>A p.Ser429Arg missense_variant 2/2 ENST00000287020.7 NP_001001557.1 Q6KF10A0A0S2A5D6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GDF6ENST00000287020.7 linkuse as main transcriptc.1287C>A p.Ser429Arg missense_variant 2/21 NM_001001557.4 ENSP00000287020.4 Q6KF10

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Multiple synostoses syndrome 4 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 28, 2018- -
Uncertain significance, criteria provided, single submittercurationSIB Swiss Institute of BioinformaticsOct 15, 2018This variant is interpreted as Uncertain Significance - Insufficient Evidence, for Multiple synostoses syndrome 4, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1-Moderate => PP1 upgraded in strength to Moderate. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
T
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.29
T
M_CAP
Uncertain
0.26
D
MetaRNN
Uncertain
0.50
T
MetaSVM
Uncertain
0.75
D
MutationTaster
Benign
1.0
D
Vest4
0.50
MVP
0.84
ClinPred
1.0
D
GERP RS
4.1

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: rs1554571225; hg19: chr8-97156872; API