12-55748864-C-G

Position:

• chr12-55748864-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005811.5(GDF11):​c.724C>G​(p.Gln242Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,886 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GDF11 NM_005811.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25605977).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF11	NM_005811.5	c.724C>G	p.Gln242Glu	missense_variant	2/3	ENST00000257868.10	NP_005802.1
GDF11	XM_006719194.4	c.724C>G	p.Gln242Glu	missense_variant	2/4		XP_006719257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF11	ENST00000257868.10	c.724C>G	p.Gln242Glu	missense_variant	2/3	1	NM_005811.5	ENSP00000257868.5
GDF11	ENST00000546799.1	c.640C>G	p.Gln214Glu	missense_variant	2/4	1		ENSP00000448390.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460886 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726736

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Feb 10, 2022

The c.724C>G (p.Q242E) alteration is located in exon 2 (coding exon 2) of the GDF11 gene. This alteration results from a C to G substitution at nucleotide position 724, causing the glutamine (Q) at amino acid position 242 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	0.16
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.14
Sift	Benign	0.24	T
Sift4G	Benign	0.63	T
Polyphen		0.25	B
Vest4		0.29
MutPred		0.39		Loss of MoRF binding (P = 0.0305);
MVP		0.58
MPC		1.3
ClinPred		0.65	D
GERP RS		4.8
Varity_R		0.29
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-56142648;