12-55743400-CGCGGCGGCG-C

Variant names:

• chr12-55743400-CGCGGCGGCG-C
• rs759951553
• NM_005811.5:c.108_116delGGCGGCGGC

Variant summary

Our verdict is Likely benign. The variant received -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
• 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: Likely_benign. The variant received -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 VariationId is 3034015.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 255 Unknown,AD gene.

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.108_116delGGCGGCGGC	p.Ala37_Ala39del	disruptive_inframe_deletion	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.108_116delGGCGGCGGC	p.Ala37_Ala39del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000257868.5	O95390
	GDF11	ENST00000546799.1	TSL:1	c.24_32delGGCGGCGGC	p.Ala9_Ala11del	disruptive_inframe_deletion	Exon 1 of 4	ENSP00000448390.1	H0YI30

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

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

African (AFR) AF: 0.000563 AC: 9 AN: 15978

American (AMR) AF: 0.00212 AC: 3 AN: 1414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5406

East Asian (EAS) AF: 0.00463 AC: 19 AN: 4100

South Asian (SAS) AF: 0.000172 AC: 3 AN: 17416

European-Finnish (FIN) AF: 0.0101 AC: 13 AN: 1288

Middle Eastern (MID) AF: 0.000594 AC: 1 AN: 1684

European-Non Finnish (NFE) AF: 0.00313 AC: 2413 AN: 771810

Other (OTH) AF: 0.00168 AC: 47 AN: 27986

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

African (AFR) AF: 0.000811 AC: 33 AN: 40696

American (AMR) AF: 0.000543 AC: 8 AN: 14742

Ashkenazi Jewish (ASJ) AF: 0.000296 AC: 1 AN: 3384

East Asian (EAS) AF: 0.00359 AC: 18 AN: 5018

South Asian (SAS) AF: 0.00 AC: 0 AN: 4770

European-Finnish (FIN) AF: 0.00120 AC: 10 AN: 8316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00273 AC: 179 AN: 65598

Other (OTH) AF: 0.00295 AC: 6 AN: 2036

Alfa AF: 0.00 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	GDF11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=189/11	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;