2-20667622-C-A

Position:

• chr2-20667622-C-A

Variant summary

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

The NM_182828.4(GDF7):​c.383C>A​(p.Ala128Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GDF7 NM_182828.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

Genes affected

GDF7 (HGNC:4222): (growth differentiation factor 7) 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 may play a role in the differentiation of tendon cells and spinal cord interneurons. A mutation in this gene may be associated with increased risk for Barrett's esophagus and esophageal adenocarcinoma. [provided by RefSeq, Sep 2016]

ACMG classification

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
GDF7	NM_182828.4	c.383C>A	p.Ala128Glu	missense_variant	1/2	ENST00000272224.5	NP_878248.2
GDF7	XM_047443522.1	c.-814C>A		upstream_gene_variant			XP_047299478.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF7	ENST00000272224.5	c.383C>A	p.Ala128Glu	missense_variant	1/2	1	NM_182828.4	ENSP00000272224.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1347910 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 670366

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Nov 25, 2024

The c.383C>A (p.A128E) alteration is located in exon 1 (coding exon 1) of the GDF7 gene. This alteration results from a C to A substitution at nucleotide position 383, causing the alanine (A) at amino acid position 128 to be replaced by a glutamic acid (E). 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	Benign	0.32
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.18
Sift	Benign	0.27	T
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.23
MutPred		0.42		Loss of helix (P = 0.0376);
MVP		0.80
ClinPred		0.88	D
GERP RS		2.9
Varity_R		0.23
gMVP		0.48

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: rs781520892; hg19: chr2-20867382;