rs745318781

Variant names:

• chr7-27108450-C-A
• rs745318781
• NM_153631.3:c.797G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-27108450-C-A
• chr7-27108450-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_153631.3(HOXA3):​c.797G>T​(p.Arg266Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: HOXA3 NM_153631.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.66
• Publications: 5 publications found

Genes affected

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]

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]

ENSG00000293629 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30501324).
• BS2: High AC in GnomAdExome4 at 40 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153631.3. 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
	HOXA3	NM_153631.3	MANE Select	c.797G>T	p.Arg266Leu	missense	Exon 6 of 6	NP_705895.1	O43365
	HOXA3	NM_001384335.1		c.797G>T	p.Arg266Leu	missense	Exon 7 of 7	NP_001371264.1	O43365
	HOXA3	NM_001384336.1		c.797G>T	p.Arg266Leu	missense	Exon 5 of 5	NP_001371265.1	O43365

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA3	ENST00000612286.5	TSL:2 MANE Select	c.797G>T	p.Arg266Leu	missense	Exon 6 of 6	ENSP00000484411.1	O43365
	HOXA3	ENST00000396352.8	TSL:1	c.797G>T	p.Arg266Leu	missense	Exon 3 of 3	ENSP00000379640.3	O43365
	HOXA3	ENST00000317201.7	TSL:5	c.797G>T	p.Arg266Leu	missense	Exon 5 of 5	ENSP00000324884.2	O43365

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251190 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461748 Hom.: 0 Cov.: 33 AF XY: 0.0000289 AC XY: 21 AN XY: 727180

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.000957 AC: 38 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111944

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74454

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

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	Uncertain	0.39
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.57
Sift	Benign	0.10	T
Sift4G	Benign	0.34	T
Polyphen		1.0	D
Vest4		0.25
MutPred		0.27		Loss of solvent accessibility (P = 0.0052)
MVP		0.89
MPC		0.68
ClinPred		0.69	D
GERP RS		5.6
Varity_R		0.52
gMVP		0.74
Mutation Taster		=55/45	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: rs745318781; hg19: chr7-27148069; COSMIC: COSV100415279; COSMIC: COSV100415279;