7-27199209-T-G

Position:

• chr7-27199209-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000522.5(HOXA13):​c.869A>C​(p.Tyr290Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Y290Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HOXA13 NM_000522.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.97

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755
• PP5: Variant 7-27199209-T-G is Pathogenic according to our data. Variant chr7-27199209-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1801485.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXA13	NM_000522.5	c.869A>C	p.Tyr290Ser	missense_variant	1/2	ENST00000649031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXA13	ENST00000649031.1	c.869A>C	p.Tyr290Ser	missense_variant	1/2		NM_000522.5	P1
HOTTIP	ENST00000421733.1	n.167+468T>G		intron_variant, non_coding_transcript_variant		5
HOTTIP	ENST00000605136.6			upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hand-foot-genital syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics

Oct 03, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
Polyphen		1.0	D;D
Vest4		0.44
MutPred		0.40		Gain of disorder (P = 0.0087);Gain of disorder (P = 0.0087);
MVP		0.75
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.83

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: chr7-27238828;