12-55743611-G-A

Position:

• chr12-55743611-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005811.5(GDF11):​c.295G>A​(p.Val99Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: GDF11 NM_005811.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47

Genes affected

GDF11 (HGNC:4216): (growth differentiation factor 11) 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 plays a role in the development of the nervous and other organ systems, and may regulate aging. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2916871).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF11	NM_005811.5	c.295G>A	p.Val99Met	missense_variant	1/3	ENST00000257868.10	NP_005802.1
GDF11	XM_006719194.4	c.295G>A	p.Val99Met	missense_variant	1/4		XP_006719257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF11	ENST00000257868.10	c.295G>A	p.Val99Met	missense_variant	1/3	1	NM_005811.5	ENSP00000257868.5
GDF11	ENST00000546799.1	c.211G>A	p.Val71Met	missense_variant	1/4	1		ENSP00000448390.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

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

Jul 12, 2023

The c.295G>A (p.V99M) alteration is located in exon 1 (coding exon 1) of the GDF11 gene. This alteration results from a G to A substitution at nucleotide position 295, causing the valine (V) at amino acid position 99 to be replaced by a methionine (M). 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	0.18
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.2	L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.28
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.87	P
Vest4		0.29
MutPred		0.40		Gain of MoRF binding (P = 0.0911);
MVP		0.53
MPC		1.4
ClinPred		0.60	D
GERP RS		2.8
Varity_R		0.067
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-56137395;