NM_002141.5:c.243G>C

Variant names:

• chr7-27130491-C-G
• rs761518289
• NM_002141.5:c.243G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_002141.5(HOXA4):​c.243G>C​(p.Glu81Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,279,822 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0020 (1 hom.)
• Consequence: HOXA4 NM_002141.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.24
• Publications: 2 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051670074).
• BP6: Variant 7-27130491-C-G is Benign according to our data. Variant chr7-27130491-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3034411.Status of the report is no_assertion_criteria_provided, 0 stars.

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.243G>C	p.Glu81Asp	missense	Exon 1 of 2	NP_002132.3
	HOXA3	NM_153631.3	MANE Select	c.-389-3421G>C		intron	N/A	NP_705895.1	O43365
	HOXA3	NM_001384335.1		c.-505-3421G>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.243G>C	p.Glu81Asp	missense	Exon 1 of 2	ENSP00000353151.5	Q00056
	HOXA4	ENST00000610970.1	TSL:1	c.243G>C	p.Glu81Asp	missense	Exon 1 of 2	ENSP00000479166.1	Q00056
	HOXA3	ENST00000612286.5	TSL:2 MANE Select	c.-389-3421G>C		intron	N/A	ENSP00000484411.1	O43365

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 192 AN: 150284 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00251

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00199

Gnomad OTH AF: 0.00242

GnomAD2 exomes AF: 0.00152 AC: 23 AN: 15170 AF XY: 0.00151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000240

Gnomad NFE exome AF: 0.00358

Gnomad OTH exome AF: 0.00256

GnomAD4 exome AF: 0.00198 AC: 2235 AN: 1129430 Hom.: 1 Cov.: 39 AF XY: 0.00200 AC XY: 1086 AN XY: 543062

African (AFR) AF: 0.000179 AC: 4 AN: 22300

American (AMR) AF: 0.00165 AC: 17 AN: 10286

Ashkenazi Jewish (ASJ) AF: 0.0000710 AC: 1 AN: 14092

East Asian (EAS) AF: 0.00 AC: 0 AN: 24480

South Asian (SAS) AF: 0.00 AC: 0 AN: 33638

European-Finnish (FIN) AF: 0.000171 AC: 5 AN: 29264

Middle Eastern (MID) AF: 0.000328 AC: 1 AN: 3048

European-Non Finnish (NFE) AF: 0.00224 AC: 2125 AN: 947496

Other (OTH) AF: 0.00183 AC: 82 AN: 44826

GnomAD4 genome AF: 0.00128 AC: 192 AN: 150392 Hom.: 0 Cov.: 34 AF XY: 0.00105 AC XY: 77 AN XY: 73434

African (AFR) AF: 0.000339 AC: 14 AN: 41324

American (AMR) AF: 0.00251 AC: 38 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000101 AC: 1 AN: 9860

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

European-Non Finnish (NFE) AF: 0.00199 AC: 134 AN: 67360

Other (OTH) AF: 0.00239 AC: 5 AN: 2092

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.00149

ExAC AF: 0.000627 AC: 46

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	HOXA4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.87
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.81	L
PhyloP100		-1.2
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.089
Sift	Benign	0.32	T
Sift4G	Benign	0.34	T
Polyphen		0.90	P
Vest4		0.27
MutPred		0.17		Loss of helix (P = 0.1299)
MVP		0.52
MPC		0.63
ClinPred		0.039	T
GERP RS		-0.35
PromoterAI		0.045	Neutral
Varity_R		0.060
gMVP		0.16
Mutation Taster		=92/8	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: rs761518289; hg19: chr7-27170110; COSMIC: COSV99073506; COSMIC: COSV99073506;