12-55743758-G-C

Position:

• chr12-55743758-G-C

Variant summary

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

The NM_005811.5(GDF11):​c.442G>C​(p.Glu148Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GDF11 NM_005811.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.62

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=0.40324634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF11	NM_005811.5	c.442G>C	p.Glu148Gln	missense_variant	1/3	ENST00000257868.10	NP_005802.1
GDF11	XM_006719194.4	c.442G>C	p.Glu148Gln	missense_variant	1/4		XP_006719257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF11	ENST00000257868.10	c.442G>C	p.Glu148Gln	missense_variant	1/3	1	NM_005811.5	ENSP00000257868.5
GDF11	ENST00000546799.1	c.358G>C	p.Glu120Gln	missense_variant	1/4	1		ENSP00000448390.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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 17, 2021

The c.442G>C (p.E148Q) alteration is located in exon 1 (coding exon 1) of the GDF11 gene. This alteration results from a G to C substitution at nucleotide position 442, causing the glutamic acid (E) at amino acid position 148 to be replaced by a glutamine (Q). 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	0.13
BayesDel_addAF	Benign	-0.0084	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.015	D
Sift4G	Benign	0.076	T
Polyphen		0.99	D
Vest4		0.17
MutPred		0.57		Gain of catalytic residue at A146 (P = 0.0155);
MVP		0.73
MPC		1.8
ClinPred		0.92	D
GERP RS		2.7
Varity_R		0.52
gMVP		0.80

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: chr12-56137542;