10-47309850-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004962.5(GDF10):c.374C>T(p.Ser125Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000238 in 1,612,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: GDF10 NM_004962.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.78

Genes affected

GDF10 (HGNC:4215): (growth differentiation factor 10) 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 promotes neural repair after stroke. Additionally, this protein may act as a tumor suppressor and reduced expression of this gene is associated with oral cancer. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF10	NM_004962.5	c.374C>T	p.Ser125Leu	missense_variant	2/3	ENST00000580279.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF10	ENST00000580279.2	c.374C>T	p.Ser125Leu	missense_variant	2/3	1	NM_004962.5	P1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000121 AC: 30 AN: 247710 Hom.: 0 AF XY: 0.000156 AC XY: 21 AN XY: 134906

Gnomad AFR exome AF: 0.0000656

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000197

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000240 AC: 351 AN: 1460600 Hom.: 0 Cov.: 32 AF XY: 0.000257 AC XY: 187 AN XY: 726620

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000273

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.000256 AC XY: 19 AN XY: 74362

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000365 Hom.: 0

Bravo AF: 0.000159

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2022

The c.374C>T (p.S125L) alteration is located in exon 2 (coding exon 2) of the GDF10 gene. This alteration results from a C to T substitution at nucleotide position 374, causing the serine (S) at amino acid position 125 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Pathogenic	0.80	D
Sift4G	Uncertain	0.0030	D
Vest4		0.74
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs145891412; hg19: chr10-48429512;