Variant 7-27108678-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_153631.3(HOXA3):c.569C>G(p.Ser190Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,609,984 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

HOXA3
NM_153631.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.57

Variant links:

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]

HOXA3 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 -4 ACMG points.

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXA3	NM_153631.3 linkuse as main transcript	c.569C>G	p.Ser190Trp	missense_variant	6/6	ENST00000612286.5	NP_705895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXA3	ENST00000612286.5 linkuse as main transcript	c.569C>G	p.Ser190Trp	missense_variant	6/6	2	NM_153631.3	ENSP00000484411	P1
HOXA-AS2	ENST00000669815.1 linkuse as main transcript	n.81+593G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000153

AC:

AN:

248188

Hom.:

AF XY:

0.000179

AC XY:

AN XY:

134370

show subpopulations

Gnomad AFR exome

AF:

0.0000633

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000237

AC:

345

AN:

1457832

Hom.:

Cov.:

AF XY:

0.000251

AC XY:

182

AN XY:

724512

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.0000769

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000282

Gnomad4 OTH exome

AF:

0.000299

GnomAD4 genome

AF:

0.000118

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000169

Hom.:

Bravo

AF:

0.000174

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000149

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.569C>G (p.S190W) alteration is located in exon 4 (coding exon 2) of the HOXA3 gene. This alteration results from a C to G substitution at nucleotide position 569, causing the serine (S) at amino acid position 190 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.65

D;D;D

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

.;D;.

M_CAP

Pathogenic

0.31

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

M;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.0

D;.;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.47

MVP

0.91

MPC

1.4

ClinPred

0.75

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.58

gMVP

0.54

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