7-27130309-G-A

Position:

• chr7-27130309-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002141.5(HOXA4):​c.425C>T​(p.Pro142Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000543 in 1,086,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: HOXA4 NM_002141.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21861753).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXA4	NM_002141.5	c.425C>T	p.Pro142Leu	missense_variant	1/2	ENST00000360046.10	NP_002132.3
HOXA3	NM_153631.3	c.-389-3239C>T		intron_variant		ENST00000612286.5	NP_705895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXA4	ENST00000360046.10	c.425C>T	p.Pro142Leu	missense_variant	1/2	1	NM_002141.5	ENSP00000353151.5
HOXA3	ENST00000612286.5	c.-389-3239C>T		intron_variant		2	NM_153631.3	ENSP00000484411.1

Frequencies

GnomAD3 genomes AF: 0.0000339 AC: 5 AN: 147694 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000754

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000575 AC: 54 AN: 938624 Hom.: 0 Cov.: 28 AF XY: 0.0000569 AC XY: 25 AN XY: 439168

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: 0.0000548

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000615

Gnomad4 OTH exome AF: 0.0000595

GnomAD4 genome AF: 0.0000338 AC: 5 AN: 147800 Hom.: 0 Cov.: 34 AF XY: 0.0000417 AC XY: 3 AN XY: 71966

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000754

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2022

The c.425C>T (p.P142L) 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 425, causing the proline (P) at amino acid position 142 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	Benign	0.10
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.060	T;T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.49	.;.;T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.55	N;N;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.1	.;N;N
REVEL	Benign	0.26
Sift	Benign	0.16	.;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.0040	B;B;B
Vest4		0.13
MutPred		0.31		Loss of glycosylation at P142 (P = 0.003);Loss of glycosylation at P142 (P = 0.003);Loss of glycosylation at P142 (P = 0.003);
MVP		0.87
MPC		1.2
ClinPred		0.31	T
GERP RS		0.50
Varity_R		0.052
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

LitVar

Other links and lift over

dbSNP: rs1159260195; hg19: chr7-27169928;