NM_005522.5:c.194A>C

Variant names:

Variant summary

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

The NM_005522.5(HOXA1):c.194A>C(p.His65Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,604,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

HOXA1
NM_005522.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.51

Variant links:

Genes affected

HOXA1 (HGNC:5099): (homeobox A1) 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. The encoded protein may be involved in the placement of hindbrain segments in the proper location along the anterior-posterior axis during development. Two transcript variants encoding two different isoforms have been found for this gene, with only one of the isoforms containing the homeodomain region. [provided by RefSeq, Jul 2008]

HOXA1 links:

HOTAIRM1 (HGNC:37117): (HOXA transcript antisense RNA, myeloid-specific 1) This non-coding locus is located in the HOX gene cluster. Transcription of this locus is induced by retinoic acid, and transcripts likely function in regulation of myelopoiesis through transcriptional activation of several genes in the HOXA cluster, in addition to several beta-2 integrins. [provided by RefSeq, Jan 2013]

HOTAIRM1 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=0.012768209).

BP6

Variant 7-27095719-T-G is Benign according to our data. Variant chr7-27095719-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 359969.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXA1	NM_005522.5 link	c.194A>C	p.His65Pro	missense_variant	Exon 1 of 2	ENST00000643460.2	NP_005513.2	P49639
HOXA1	NM_153620.3 link	c.194A>C	p.His65Pro	missense_variant	Exon 1 of 3		NP_705873.3	P49639

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HOXA1	ENST00000643460.2 link	c.194A>C	p.His65Pro	missense_variant	Exon 1 of 2		NM_005522.5	ENSP00000494260.2	A0A2R8Y4R9
HOXA1	ENST00000355633.5 link	c.194A>C	p.His65Pro	missense_variant	Exon 1 of 3	1		ENSP00000347851.5	E7ERT8
HOTAIRM1	ENST00000495032.1 link	n.26+47T>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.000365

AC:

AN:

150718

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000729

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000662

Gnomad ASJ

AF:

0.00145

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000212

Gnomad FIN

AF:

0.0000959

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000652

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000439

AC:

108

AN:

245984

Hom.:

AF XY:

0.000413

AC XY:

AN XY:

133314

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00194

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000637

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000524

AC:

762

AN:

1453656

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

379

AN XY:

723106

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000180

Gnomad4 ASJ exome

AF:

0.00213

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000221

Gnomad4 FIN exome

AF:

0.0000379

Gnomad4 NFE exome

AF:

0.000589

Gnomad4 OTH exome

AF:

0.000399

GnomAD4 genome

AF:

0.000365

AC:

AN:

150832

Hom.:

Cov.:

AF XY:

0.000272

AC XY:

AN XY:

73634

show subpopulations

Gnomad4 AFR

AF:

0.0000727

Gnomad4 AMR

AF:

0.0000661

Gnomad4 ASJ

AF:

0.00145

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000212

Gnomad4 FIN

AF:

0.0000959

Gnomad4 NFE

AF:

0.000652

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000595

Hom.:

Bravo

AF:

0.000336

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000387

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Bosley-Salih-Alorainy syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 10, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.71

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.56

.;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Uncertain

-0.27

PrimateAI

Benign

0.43

PROVEAN

Benign

1.2

N;.;N

REVEL

Uncertain

0.32

Sift

Benign

0.42

T;.;T

Sift4G

Benign

0.33

T;.;T

Polyphen

0.95

.;.;P

Vest4

0.24

MVP

0.97

MPC

1.2

ClinPred

0.015

GERP RS

4.1

gMVP

0.47

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