7-27199294-C-A

Position:

• chr7-27199294-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000522.5(HOXA13):​c.784G>T​(p.Gly262Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G262S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HOXA13 NM_000522.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXA13	NM_000522.5	c.784G>T	p.Gly262Cys	missense_variant	1/2	ENST00000649031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXA13	ENST00000649031.1	c.784G>T	p.Gly262Cys	missense_variant	1/2		NM_000522.5	P1
HOTTIP	ENST00000605136.6	n.50C>A		non_coding_transcript_exon_variant	1/2	2
HOTTIP	ENST00000421733.1	n.167+553C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461712 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.784G>T (p.G262C) alteration is located in exon 1 (coding exon 1) of the HOXA13 gene. This alteration results from a G to T substitution at nucleotide position 784, causing the glycine (G) at amino acid position 262 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	0.0019	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Uncertain	0.095	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	0.77	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.4	.;D
REVEL	Benign	0.18
Sift	Uncertain	0.017	.;D
Sift4G	Uncertain	0.013	.;D
Polyphen		1.0	D;D
Vest4		0.56
MutPred		0.38		Gain of stability (P = 0.0068);Gain of stability (P = 0.0068);
MVP		0.80
ClinPred		0.97	D
GERP RS		2.8
Varity_R		0.42
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr7-27238913;