7-27130358-G-C

Variant names:

• chr7-27130358-G-C
• rs561219190
• NM_002141.5:c.376C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002141.5(HOXA4):​c.376C>G​(p.Pro126Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,134,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: HOXA4 NM_002141.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17951483).

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.376C>G	p.Pro126Ala	missense	Exon 1 of 2	NP_002132.3
	HOXA3	NM_153631.3	MANE Select	c.-389-3288C>G		intron	N/A	NP_705895.1	O43365
	HOXA3	NM_001384335.1		c.-505-3288C>G		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.376C>G	p.Pro126Ala	missense	Exon 1 of 2	ENSP00000353151.5	Q00056
	HOXA4	ENST00000610970.1	TSL:1	c.376C>G	p.Pro126Ala	missense	Exon 1 of 2	ENSP00000479166.1	Q00056
	HOXA3	ENST00000612286.5	TSL:2 MANE Select	c.-389-3288C>G		intron	N/A	ENSP00000484411.1	O43365

Frequencies

GnomAD3 genomes AF: 0.000626 AC: 93 AN: 148488 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000335

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: 0.00

Gnomad OTH AF: 0.000490

GnomAD4 exome AF: 0.0000609 AC: 60 AN: 985766 Hom.: 0 Cov.: 39 AF XY: 0.0000714 AC XY: 33 AN XY: 462482

African (AFR) AF: 0.00250 AC: 47 AN: 18818

American (AMR) AF: 0.000185 AC: 1 AN: 5392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9838

East Asian (EAS) AF: 0.00 AC: 0 AN: 17492

South Asian (SAS) AF: 0.00 AC: 0 AN: 18684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2392

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 859610

Other (OTH) AF: 0.000328 AC: 12 AN: 36636

GnomAD4 genome AF: 0.000646 AC: 96 AN: 148594 Hom.: 0 Cov.: 34 AF XY: 0.000691 AC XY: 50 AN XY: 72382

African (AFR) AF: 0.00219 AC: 90 AN: 41154

American (AMR) AF: 0.000334 AC: 5 AN: 14956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66584

Other (OTH) AF: 0.000484 AC: 1 AN: 2064

Alfa AF: 0.000569 Hom.: 0

Bravo AF: 0.000782

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	0.057
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.21
Sift	Benign	0.052	T
Sift4G	Benign	0.40	T
Polyphen		0.012	B
Vest4		0.15
MutPred		0.33		Loss of relative solvent accessibility (P = 0.0071)
MVP		0.80
MPC		0.96
ClinPred		0.24	T
GERP RS		3.1
PromoterAI		-0.11	Neutral
Varity_R		0.066
gMVP		0.18
Mutation Taster		=86/14	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

dbSNP: rs561219190; hg19: chr7-27169977;