chr7-27184749-C-G

Variant names:

Variant summary

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

The NM_005523.6(HOXA11):c.396G>C(p.Arg132Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000433 in 1,613,838 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 1 hom. )

Consequence

HOXA11
NM_005523.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 0.960

Variant links:

Genes affected

HOXA11 (HGNC:5101): (homeobox A11) 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. This gene is involved in the regulation of uterine development and is required for female fertility. Mutations in this gene can cause radio-ulnar synostosis with amegakaryocytic thrombocytopenia. [provided by RefSeq, Jul 2008]

HOXA11 links:

HOXA11-AS (HGNC:24957): (HOXA11 antisense RNA) This gene produces a long non-coding RNA in antisense to transcription of the homeobox A11 gene. This transcript may associate with chromatin factors such as Polycomb repressive complex and act as a sponge for microRNAs, thereby participating in the regulation of expression of target genes. High levels of this transcript may be associated with tumor progression. [provided by RefSeq, Dec 2017]

HOXA11-AS 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 77 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXA11	NM_005523.6 link	c.396G>C	p.Arg132Ser	missense_variant	Exon 1 of 2	ENST00000006015.4	NP_005514.1	P31270

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXA11	ENST00000006015.4 link	c.396G>C	p.Arg132Ser	missense_variant	Exon 1 of 2	1	NM_005523.6	ENSP00000006015.3		P31270

Frequencies

GnomAD3 genomes

AF:

0.000506

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000454

AC:

113

AN:

248816

Hom.:

AF XY:

0.000474

AC XY:

AN XY:

135030

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000978

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000425

AC:

621

AN:

1461500

Hom.:

Cov.:

AF XY:

0.000486

AC XY:

353

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000245

Gnomad4 NFE exome

AF:

0.000536

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000505

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00106

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000609

Hom.:

Bravo

AF:

0.000325

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000568

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Radioulnar synostosis with amegakaryocytic thrombocytopenia 1

Uncertain:1

Nov 03, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HOXA11 NM_005523.5 exon 1 p.Arg132Ser (c.396G>C): This variant has not been reported in the literature but is present in 0.1% (72/68034) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/7-27184749-C-G?dataset=gnomad_r3). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

HOXA11-related disorder

Benign:1

Jun 13, 2023

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

Pathogenic

0.98

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.71

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.60

MutationAssessor

Pathogenic

3.6

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.47

Sift

Benign

0.036

Sift4G

Uncertain

0.043

Polyphen

0.86

Vest4

0.87

MutPred

0.50

Loss of methylation at R132 (P = 0.0427);

MVP

0.92

MPC

2.1

ClinPred

0.61

GERP RS

2.3

Varity_R

0.71

gMVP

0.79

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