7-27130491-C-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

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. 13/20 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

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.24

Variant links:

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]

HOXA4 links:

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]

HOXA3 links:

ENSG00000273433 (HGNC:):

ENSG00000273433 links:

HOXA-AS3 (HGNC:43748): (HOXA cluster antisense RNA 3)

HOXA-AS3 links:

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]

HOXA-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id is 3034411.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXA4	NM_002141.5 link	c.243G>C	p.Glu81Asp	missense_variant	Exon 1 of 2	ENST00000360046.10	NP_002132.3	Q00056
HOXA3	NM_153631.3 link	c.-389-3421G>C		intron_variant	Intron 2 of 5	ENST00000612286.5	NP_705895.1	O43365A4D182A0A024RA33B3KPN8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXA4	ENST00000360046.10 link	c.243G>C	p.Glu81Asp	missense_variant	Exon 1 of 2	1	NM_002141.5	ENSP00000353151.5		Q00056
HOXA3	ENST00000612286.5 link	c.-389-3421G>C		intron_variant	Intron 2 of 5	2	NM_153631.3	ENSP00000484411.1		O43365

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

192

AN:

150284

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00152

AC:

AN:

15170

Hom.:

AF XY:

0.00151

AC XY:

AN XY:

8596

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.00200

AC XY:

1086

AN XY:

543062

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00165

Gnomad4 ASJ exome

AF:

0.0000710

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000171

Gnomad4 NFE exome

AF:

0.00224

Gnomad4 OTH exome

AF:

0.00183

GnomAD4 genome

AF:

0.00128

AC:

192

AN:

150392

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

73434

show subpopulations

Gnomad4 AFR

AF:

0.000339

Gnomad4 AMR

AF:

0.00251

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000101

Gnomad4 NFE

AF:

0.00199

Gnomad4 OTH

AF:

0.00239

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.00149

ExAC

AF:

0.000627

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HOXA4-related disorder

Benign:1

Apr 09, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.052

T;T;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.41

.;.;T

MetaRNN

Benign

0.0052

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.81

L;L;L

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.22

.;N;N

REVEL

Benign

0.089

Sift

Benign

0.32

.;T;T

Sift4G

Benign

0.34

T;T;T

Polyphen

0.90

P;P;P

Vest4

0.27

MutPred

0.17

Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);

MVP

0.52

MPC

0.63

ClinPred

0.039

GERP RS

-0.35

Varity_R

0.060

gMVP

0.16

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over