chr12-55743400-C-CGCGGCGGCGGCGGCGGCGGCG

Variant names:

• chr12-55743400-C-CGCGGCGGCGGCGGCGGCGGCG
• rs759951553
• NM_005811.5:c.96_116dupGGCGGCGGCGGCGGCGGCGGC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_005811.5(GDF11):​c.96_116dupGGCGGCGGCGGCGGCGGCGGC​(p.Ala33_Ala39dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GDF11 NM_005811.5 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005811.5

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.96_116dupGGCGGCGGCGGCGGCGGCGGC	p.Ala33_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.96_116dupGGCGGCGGCGGCGGCGGCGGC	p.Ala33_Ala39dup	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000257868.5	O95390
	GDF11	ENST00000546799.1	TSL:1	c.12_32dupGGCGGCGGCGGCGGCGGCGGC	p.Ala5_Ala11dup	disruptive_inframe_insertion	Exon 1 of 4	ENSP00000448390.1	H0YI30

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000354 AC: 3 AN: 847110 Hom.: 0 Cov.: 28 AF XY: 0.00000254 AC XY: 1 AN XY: 393726

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 15978

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5408

East Asian (EAS) AF: 0.00 AC: 0 AN: 4100

South Asian (SAS) AF: 0.00 AC: 0 AN: 17416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1684

European-Non Finnish (NFE) AF: 0.00000389 AC: 3 AN: 771830

Other (OTH) AF: 0.00 AC: 0 AN: 27990

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000568638), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.39

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;