12-55743400-CGCGGCGGCGGCGGCGGCG-CGCGGCGGCGGCGGCGGCGGCG

Variant names:

• chr12-55743400-C-CGCG
• rs759951553
• NM_005811.5:c.114_116dupGGC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP3 BA1

The NM_005811.5(GDF11):​c.114_116dupGGC​(p.Ala39dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 992,768 control chromosomes in the GnomAD database, including 23 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0041 (17 hom., cov: 30)
  • Exomes 𝑓: 0.0013 (6 hom.)
• Consequence: GDF11 NM_005811.5 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.392

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 -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005811.5
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF11	NM_005811.5	c.114_116dupGGC	p.Ala39dup	disruptive_inframe_insertion	Exon 1 of 3	ENST00000257868.10	NP_005802.1
GDF11	XM_006719194.4	c.114_116dupGGC	p.Ala39dup	disruptive_inframe_insertion	Exon 1 of 4		XP_006719257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF11	ENST00000257868.10	c.114_116dupGGC	p.Ala39dup	disruptive_inframe_insertion	Exon 1 of 3	1	NM_005811.5	ENSP00000257868.5
GDF11	ENST00000546799.1	c.30_32dupGGC	p.Ala11dup	disruptive_inframe_insertion	Exon 1 of 4	1		ENSP00000448390.1

Frequencies

GnomAD3 genomes AF: 0.00411 AC: 598 AN: 145654 Hom.: 17 Cov.: 30

Gnomad AFR AF: 0.00214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00102

Gnomad ASJ AF: 0.00621

Gnomad EAS AF: 0.0648

Gnomad SAS AF: 0.00900

Gnomad FIN AF: 0.00397

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000975

Gnomad OTH AF: 0.00397

GnomAD4 exome AF: 0.00133 AC: 1129 AN: 847014 Hom.: 6 Cov.: 28 AF XY: 0.00129 AC XY: 506 AN XY: 393682

Gnomad4 AFR exome AF: 0.00244

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00351

Gnomad4 EAS exome AF: 0.0576

Gnomad4 SAS exome AF: 0.00540

Gnomad4 FIN exome AF: 0.00155

Gnomad4 NFE exome AF: 0.000780

Gnomad4 OTH exome AF: 0.00468

GnomAD4 genome AF: 0.00410 AC: 597 AN: 145754 Hom.: 17 Cov.: 30 AF XY: 0.00480 AC XY: 340 AN XY: 70868

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00102

Gnomad4 ASJ AF: 0.00621

Gnomad4 EAS AF: 0.0650

Gnomad4 SAS AF: 0.00901

Gnomad4 FIN AF: 0.00397

Gnomad4 NFE AF: 0.000976

Gnomad4 OTH AF: 0.00344

ClinVar

Not reported in ClinVar

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;