7-27199336-C-CA

Position:

• chr7-27199336-C-CA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000522.5(HOXA13):​c.741_742insT​(p.Gly248TrpfsTer73) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HOXA13 NM_000522.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.21

Genes affected

HOXA13 (HGNC:5102): (homeobox A13) In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. Expansion of a polyalanine tract in the encoded protein can cause hand-foot-uterus syndrome, also known as hand-foot-genital syndrome. [provided by RefSeq, Jul 2008]

HOTTIP (HGNC:37461): (HOXA distal transcript antisense RNA) This gene produces a long RNA in antisense to the HOXA gene cluster. This transcript may regulate expression of HOXA genes in cis. This gene is upregulated in tumors and is implicated in the promotion of cell proliferation. [provided by RefSeq, Dec 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-27199336-C-CA is Pathogenic according to our data. Variant chr7-27199336-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1805747.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXA13	NM_000522.5	c.741_742insT	p.Gly248TrpfsTer73	frameshift_variant	1/2	ENST00000649031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXA13	ENST00000649031.1	c.741_742insT	p.Gly248TrpfsTer73	frameshift_variant	1/2		NM_000522.5	P1
HOTTIP	ENST00000421733.1	n.167+596dup		intron_variant, non_coding_transcript_variant		5
HOTTIP	ENST00000605136.6	n.86+7dup		splice_region_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hand-foot-genital syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 21, 2020

A heterozygous duplication variant was identified, NM_000522.4(HOXA13):c.741dup in exon 1 of 2 of the HOXA13 gene. This duplication is predicted to cause a frameshift from amino acid position 248 introducing a stop codon downstream; NP_000513.2(HOXA13):p.(Gly248Trpfs*73), resulting in loss of normal protein function through truncation (one third of the protein, including the functional homeodomain (NCBI, PDB)). The variant is not present in the gnomAD population database and has not been previously observed in clinical cases. Other truncating variants downstream of this variant, have been reported as pathogenic in individuals with hand and foot abnormalities (ClinVar, Goodman, FR. et al. (2000), Mortlock, DP. and Innis, JW. (1997)). Based on information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-27238955;