NM_005811.5:c.419A>G

Variant names:

• chr12-55743735-A-G
• rs750059741
• NM_005811.5:c.419A>G

Variant summary

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

The NM_005811.5(GDF11):​c.419A>G​(p.Glu140Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000695 in 1,438,772 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GDF11 NM_005811.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.09

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF11	NM_005811.5	c.419A>G	p.Glu140Gly	missense_variant	Exon 1 of 3	ENST00000257868.10	NP_005802.1
GDF11	XM_006719194.4	c.419A>G	p.Glu140Gly	missense_variant	Exon 1 of 4		XP_006719257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF11	ENST00000257868.10	c.419A>G	p.Glu140Gly	missense_variant	Exon 1 of 3	1	NM_005811.5	ENSP00000257868.5
GDF11	ENST00000546799.1	c.335A>G	p.Glu112Gly	missense_variant	Exon 1 of 4	1		ENSP00000448390.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000443 AC: 1 AN: 225890 Hom.: 0 AF XY: 0.00000802 AC XY: 1 AN XY: 124704

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000947

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1438772 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 715758

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.93	P
Vest4		0.43
MutPred		0.63		Gain of catalytic residue at H136 (P = 0.0107);
MVP		0.66
MPC		2.4
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.78
gMVP		0.94

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: rs750059741; hg19: chr12-56137519;