chr12-55743400-CGCG-C

Position:

• chr12-55743400-CGCG-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BS1 BS2

The NM_005811.5(GDF11):​c.114_116del​(p.Ala41del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00696 in 965,392 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0080 (0 hom.)
• Consequence: GDF11 NM_005811.5 inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.25

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 Benign. Variant got -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005811.5
• BP6: Variant 12-55743400-CGCG-C is Benign according to our data. Variant chr12-55743400-CGCG-C is described in ClinVar as [Likely_benign]. Clinvar id is 3054165.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-55743400-CGCG-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00799 (6552/819642) while in subpopulation AMR AF= 0.0214 (29/1358). AF 95% confidence interval is 0.0153. There are 0 homozygotes in gnomad4_exome. There are 3122 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 163 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF11	NM_005811.5	c.114_116del	p.Ala41del	inframe_deletion	1/3	ENST00000257868.10
GDF11	XM_006719194.4	c.114_116del	p.Ala41del	inframe_deletion	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF11	ENST00000257868.10	c.114_116del	p.Ala41del	inframe_deletion	1/3	1	NM_005811.5	P1
GDF11	ENST00000546799.1	c.32_34del	p.Ala14del	inframe_deletion	1/4	1

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 162 AN: 145650 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000747

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.000240

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000610

Gnomad OTH AF: 0.000497

GnomAD3 exomes AF: 0.00230 AC: 1 AN: 434 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 238

Gnomad FIN exome AF: 0.00980

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00799 AC: 6552 AN: 819642 Hom.: 0 AF XY: 0.00820 AC XY: 3122 AN XY: 380906

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.0214

Gnomad4 ASJ exome AF: 0.00938

Gnomad4 EAS exome AF: 0.0125

Gnomad4 SAS exome AF: 0.00785

Gnomad4 FIN exome AF: 0.0344

Gnomad4 NFE exome AF: 0.00778

Gnomad4 OTH exome AF: 0.00816

GnomAD4 genome AF: 0.00112 AC: 163 AN: 145750 Hom.: 0 Cov.: 30 AF XY: 0.00110 AC XY: 78 AN XY: 70864

Gnomad4 AFR AF: 0.00354

Gnomad4 AMR AF: 0.000746

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000210

Gnomad4 FIN AF: 0.000240

Gnomad4 NFE AF: 0.0000610

Gnomad4 OTH AF: 0.000491

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GDF11-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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: rs759951553; hg19: chr12-56137184;