7-27108135-T-A

Variant names:

• chr7-27108135-T-A
• NM_153631.3:c.1112A>T

Variant summary

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

The NM_153631.3(HOXA3):​c.1112A>T​(p.Tyr371Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,442,264 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HOXA3 NM_153631.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.08

Genes affected

HOXA3 (HGNC:5104): (homeobox A3) 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. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

HOXA-AS2 (HGNC:43745): (HOXA cluster antisense RNA 2) This gene produces a long non-coding RNA that promotes cell proliferation. This transcript may interact with enhancer of zeste homolog 2 Polycomb repressive complex to repress gene expression. [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 rank	MANE	Protein	UniProt
HOXA3	NM_153631.3	c.1112A>T	p.Tyr371Phe	missense_variant	Exon 6 of 6	ENST00000612286.5	NP_705895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXA3	ENST00000612286.5	c.1112A>T	p.Tyr371Phe	missense_variant	Exon 6 of 6	2	NM_153631.3	ENSP00000484411.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442264 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 714860

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: 9.09e-7

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

not specified Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1112A>T (p.Y371F) alteration is located in exon 4 (coding exon 2) of the HOXA3 gene. This alteration results from a A to T substitution at nucleotide position 1112, causing the tyrosine (Y) at amino acid position 371 to be replaced by a phenylalanine (F). 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	0.091
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T;T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	.;T;.
M_CAP	Uncertain	0.090	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	0.97	L;L;L
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.7	N;.;N
REVEL	Uncertain	0.54
Sift	Benign	0.37	T;.;T
Sift4G	Benign	0.37	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.49
MutPred		0.51		Loss of phosphorylation at Y371 (P = 0.0143);Loss of phosphorylation at Y371 (P = 0.0143);Loss of phosphorylation at Y371 (P = 0.0143);
MVP		0.79
MPC		0.91
ClinPred		0.88	D
GERP RS		5.8
Varity_R		0.55
gMVP		0.40

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: chr7-27147754;