12-55743400-CGCGGCGGCGGCGGCGGCGGCGGCG-CGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3 BP6_Moderate 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. Variant has been reported in ClinVar as Likely benign (★).

• 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: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.392
• Publications: 0 publications found

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]

GDF11 Gene-Disease associations (from GenCC):

• vertebral hypersegmentation and orofacial anomalies

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005811.5
• BP6: Variant 12-55743400-C-CGCG is Benign according to our data. Variant chr12-55743400-C-CGCG is described in ClinVar as Likely_benign. ClinVar VariationId is 3910970.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0592 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005811.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF11	NM_005811.5	MANE Select	c.114_116dupGGC	p.Ala39dup	disruptive_inframe_insertion	Exon 1 of 3	NP_005802.1	O95390

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF11	ENST00000257868.10	TSL:1 MANE Select	c.114_116dupGGC	p.Ala39dup	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000257868.5	O95390
	GDF11	ENST00000546799.1	TSL:1	c.30_32dupGGC	p.Ala11dup	disruptive_inframe_insertion	Exon 1 of 4	ENSP00000448390.1	H0YI30

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 434 AF XY: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.00244 AC: 39 AN: 15976

American (AMR) AF: 0.00 AC: 0 AN: 1414

Ashkenazi Jewish (ASJ) AF: 0.00351 AC: 19 AN: 5408

East Asian (EAS) AF: 0.0576 AC: 236 AN: 4094

South Asian (SAS) AF: 0.00540 AC: 94 AN: 17410

European-Finnish (FIN) AF: 0.00155 AC: 2 AN: 1290

Middle Eastern (MID) AF: 0.00356 AC: 6 AN: 1684

European-Non Finnish (NFE) AF: 0.000780 AC: 602 AN: 771754

Other (OTH) AF: 0.00468 AC: 131 AN: 27984

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

African (AFR) AF: 0.00214 AC: 87 AN: 40696

American (AMR) AF: 0.00102 AC: 15 AN: 14742

Ashkenazi Jewish (ASJ) AF: 0.00621 AC: 21 AN: 3384

East Asian (EAS) AF: 0.0650 AC: 326 AN: 5016

South Asian (SAS) AF: 0.00901 AC: 43 AN: 4770

European-Finnish (FIN) AF: 0.00397 AC: 33 AN: 8316

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000976 AC: 64 AN: 65598

Other (OTH) AF: 0.00344 AC: 7 AN: 2036

Alfa AF: 0.000437 Hom.: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.39
Mutation Taster		=67/33	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs759951553; hg19: chr12-56137184; COSMIC: COSV105857131;