7-27130342-T-G

Variant names:

• chr7-27130342-T-G
• rs1261664747
• NM_002141.5:c.392A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002141.5(HOXA4):​c.392A>C​(p.His131Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000103 in 969,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H131R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: HOXA4 NM_002141.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.474
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17037302).

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.392A>C	p.His131Pro	missense	Exon 1 of 2	NP_002132.3
	HOXA3	NM_153631.3	MANE Select	c.-389-3272A>C		intron	N/A	NP_705895.1	O43365
	HOXA3	NM_001384335.1		c.-505-3272A>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.392A>C	p.His131Pro	missense	Exon 1 of 2	ENSP00000353151.5	Q00056
	HOXA4	ENST00000610970.1	TSL:1	c.392A>C	p.His131Pro	missense	Exon 1 of 2	ENSP00000479166.1	Q00056
	HOXA3	ENST00000612286.5	TSL:2 MANE Select	c.-389-3272A>C		intron	N/A	ENSP00000484411.1	O43365

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000103 AC: 1 AN: 969782 Hom.: 0 Cov.: 39 AF XY: 0.00000220 AC XY: 1 AN XY: 454610

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 18398

American (AMR) AF: 0.00 AC: 0 AN: 4984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9282

East Asian (EAS) AF: 0.00 AC: 0 AN: 15882

South Asian (SAS) AF: 0.00 AC: 0 AN: 18502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2340

European-Non Finnish (NFE) AF: 0.00000118 AC: 1 AN: 848950

Other (OTH) AF: 0.00 AC: 0 AN: 35668

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.83
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.47
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.21
Sift	Benign	0.16	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.31		Gain of glycosylation at S133 (P = 0.0772)
MVP		0.86
MPC		1.0
ClinPred		0.060	T
GERP RS		0.025
PromoterAI		0.14	Neutral
Varity_R		0.068
gMVP		0.19
Mutation Taster		=90/10	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: rs1261664747; hg19: chr7-27169961;