12-55743400-CGCGGCGGCG-C

Position:

• chr12-55743400-CGCGGCGGCG-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_005811.5(GDF11):​c.108_116delGGCGGCGGC​(p.Ala37_Ala39del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 992,838 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0030 (1 hom.)
• Consequence: GDF11 NM_005811.5 disruptive_inframe_deletion
• Clinical Significance: Likely benign no assertion criteria provided 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 Likely_benign. Variant got -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005811.5
• BP6: Variant 12-55743400-CGCGGCGGCG-C is Benign according to our data. Variant chr12-55743400-CGCGGCGGCG-C is described in ClinVar as [Likely_benign]. Clinvar id is 3034015.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 255 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF11	NM_005811.5	c.108_116delGGCGGCGGC	p.Ala37_Ala39del	disruptive_inframe_deletion	1/3	ENST00000257868.10	NP_005802.1
GDF11	XM_006719194.4	c.108_116delGGCGGCGGC	p.Ala37_Ala39del	disruptive_inframe_deletion	1/4		XP_006719257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF11	ENST00000257868.10	c.108_116delGGCGGCGGC	p.Ala37_Ala39del	disruptive_inframe_deletion	1/3	1	NM_005811.5	ENSP00000257868.5
GDF11	ENST00000546799.1	c.24_32delGGCGGCGGC	p.Ala9_Ala11del	disruptive_inframe_deletion	1/4	1		ENSP00000448390.1

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 254 AN: 145656 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000813

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000543

Gnomad ASJ AF: 0.000296

Gnomad EAS AF: 0.00358

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00273

Gnomad OTH AF: 0.00248

GnomAD4 exome AF: 0.00296 AC: 2508 AN: 847082 Hom.: 1 AF XY: 0.00304 AC XY: 1197 AN XY: 393710

Gnomad4 AFR exome AF: 0.000563

Gnomad4 AMR exome AF: 0.00212

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00463

Gnomad4 SAS exome AF: 0.000172

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.00313

Gnomad4 OTH exome AF: 0.00168

GnomAD4 genome AF: 0.00175 AC: 255 AN: 145756 Hom.: 0 Cov.: 30 AF XY: 0.00168 AC XY: 119 AN XY: 70870

Gnomad4 AFR AF: 0.000811

Gnomad4 AMR AF: 0.000543

Gnomad4 ASJ AF: 0.000296

Gnomad4 EAS AF: 0.00359

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00120

Gnomad4 NFE AF: 0.00273

Gnomad4 OTH AF: 0.00295

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

GDF11-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2023

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

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;