chr7-27130228-C-G

Variant names:

• chr7-27130228-C-G
• NM_002141.5:c.506G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002141.5(HOXA4):​c.506G>C​(p.Gly169Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: HOXA4 NM_002141.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31514287).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002141.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA4	NM_002141.5	MANE Select	c.506G>C	p.Gly169Ala	missense	Exon 1 of 2	NP_002132.3
	HOXA3	NM_153631.3	MANE Select	c.-389-3158G>C		intron	N/A	NP_705895.1	O43365
	HOXA3	NM_001384335.1		c.-505-3158G>C		intron	N/A	NP_001371264.1	O43365

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA4	ENST00000360046.10	TSL:1 MANE Select	c.506G>C	p.Gly169Ala	missense	Exon 1 of 2	ENSP00000353151.5	Q00056
	HOXA4	ENST00000610970.1	TSL:1	c.506G>C	p.Gly169Ala	missense	Exon 1 of 2	ENSP00000479166.1	Q00056
	HOXA3	ENST00000612286.5	TSL:2 MANE Select	c.-389-3158G>C		intron	N/A	ENSP00000484411.1	O43365

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.026
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.020	N
REVEL	Uncertain	0.29
Sift	Benign	1.0	T
Sift4G	Benign	0.52	T
Polyphen		0.80	P
Vest4		0.21
MutPred		0.24		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.91
MPC		1.3
ClinPred		0.76	D
GERP RS		3.8
PromoterAI		-0.12	Neutral
Varity_R		0.085
gMVP		0.28
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

hg19: chr7-27169847;