7-27130432-G-A

Variant names:

• chr7-27130432-G-A
• rs1785487663
• NM_002141.5:c.302C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002141.5(HOXA4):​c.302C>T​(p.Pro101Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000956 in 1,046,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 9.6e-7 (0 hom.)
• Consequence: HOXA4 NM_002141.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40

Genes affected

HOXA4 (HGNC:5105): (homeobox A4) 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. [provided by RefSeq, Jul 2008]

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]

ENSG00000273433 (HGNC:):

HOXA-AS3 (HGNC:43748): (HOXA cluster antisense RNA 3)

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34294552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXA4	NM_002141.5	c.302C>T	p.Pro101Leu	missense_variant	Exon 1 of 2	ENST00000360046.10	NP_002132.3
HOXA3	NM_153631.3	c.-389-3362C>T		intron_variant	Intron 2 of 5	ENST00000612286.5	NP_705895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXA4	ENST00000360046.10	c.302C>T	p.Pro101Leu	missense_variant	Exon 1 of 2	1	NM_002141.5	ENSP00000353151.5
HOXA3	ENST00000612286.5	c.-389-3362C>T		intron_variant	Intron 2 of 5	2	NM_153631.3	ENSP00000484411.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 9.56e-7 AC: 1 AN: 1046344 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 494378

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: 0.00000111

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.302C>T (p.P101L) alteration is located in exon 1 (coding exon 1) of the HOXA4 gene. This alteration results from a C to T substitution at nucleotide position 302, causing the proline (P) at amino acid position 101 to be replaced by a leucine (L). 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	Uncertain	0.37
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.62	.;.;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.97	L;L;L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.5	.;N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.019	.;D;D
Sift4G	Uncertain	0.058	T;T;T
Polyphen		0.19	B;B;B
Vest4		0.27
MutPred		0.41		Loss of loop (P = 0.0145);Loss of loop (P = 0.0145);Loss of loop (P = 0.0145);
MVP		0.91
MPC		1.2
ClinPred		0.80	D
GERP RS		3.3
Varity_R		0.097
gMVP		0.32

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

LitVar

Other links and lift over

dbSNP: rs1785487663; hg19: chr7-27170051;