7-27095695-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_005522.5(HOXA1):c.218G>A(p.Arg73His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.779 in 1,554,656 control chromosomes in the GnomAD database, including 459,498 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.74 ( 42759 hom., cov: 28)

Exomes 𝑓: 0.78 ( 416739 hom. )

Consequence

HOXA1
NM_005522.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.35

Publications

67 publications found

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 was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.5935766E-7).

BP6

Variant 7-27095695-C-T is Benign according to our data. Variant chr7-27095695-C-T is described in ClinVar as Benign. ClinVar VariationId is 369585.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXA1	NM_005522.5 link	c.218G>A	p.Arg73His	missense_variant	Exon 1 of 2	ENST00000643460.2	NP_005513.2	P49639
HOXA1	NM_153620.3 link	c.218G>A	p.Arg73His	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.218G>A	p.Arg73His	missense_variant	Exon 1 of 2		NM_005522.5	ENSP00000494260.2	A0A2R8Y4R9
HOXA1	ENST00000355633.5 link	c.218G>A	p.Arg73His	missense_variant	Exon 1 of 3	1		ENSP00000347851.5	E7ERT8
HOTAIRM1	ENST00000495032.1 link	n.26+23C>T		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.741

AC:

110959

AN:

149828

Hom.:

42740

Cov.:

show subpopulations

Gnomad AFR

AF:

0.475

Gnomad AMI

AF:

0.954

Gnomad AMR

AF:

0.829

Gnomad ASJ

AF:

0.836

Gnomad EAS

AF:

0.979

Gnomad SAS

AF:

0.925

Gnomad FIN

AF:

0.825

Gnomad MID

AF:

0.843

Gnomad NFE

AF:

0.829

Gnomad OTH

AF:

0.765

GnomAD2 exomes

AF:

0.757

AC:

173420

AN:

229120

AF XY:

0.760

show subpopulations

Gnomad AFR exome

AF:

0.438

Gnomad AMR exome

AF:

0.799

Gnomad ASJ exome

AF:

0.737

Gnomad EAS exome

AF:

0.911

Gnomad FIN exome

AF:

0.766

Gnomad NFE exome

AF:

0.751

Gnomad OTH exome

AF:

0.758

GnomAD4 exome

AF:

0.783

AC:

1099656

AN:

1404714

Hom.:

416739

Cov.:

AF XY:

0.785

AC XY:

549262

AN XY:

699280

show subpopulations

African (AFR)

AF:

0.450

AC:

14844

AN:

32952

American (AMR)

AF:

0.825

AC:

35792

AN:

43392

Ashkenazi Jewish (ASJ)

AF:

0.787

AC:

19706

AN:

25046

East Asian (EAS)

AF:

0.933

AC:

36132

AN:

38720

South Asian (SAS)

AF:

0.863

AC:

72101

AN:

83560

European-Finnish (FIN)

AF:

0.789

AC:

40662

AN:

51558

Middle Eastern (MID)

AF:

0.817

AC:

4557

AN:

5578

European-Non Finnish (NFE)

AF:

0.779

AC:

830667

AN:

1065822

Other (OTH)

AF:

0.778

AC:

45195

AN:

58086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

11759

23518

35278

47037

58796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20166

40332

60498

80664

100830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.740

AC:

111018

AN:

149942

Hom.:

42759

Cov.:

AF XY:

0.746

AC XY:

54622

AN XY:

73194

show subpopulations

African (AFR)

AF:

0.475

AC:

19391

AN:

40836

American (AMR)

AF:

0.830

AC:

12512

AN:

15082

Ashkenazi Jewish (ASJ)

AF:

0.836

AC:

2860

AN:

3420

East Asian (EAS)

AF:

0.979

AC:

5002

AN:

5110

South Asian (SAS)

AF:

0.926

AC:

4419

AN:

4772

European-Finnish (FIN)

AF:

0.825

AC:

8552

AN:

10364

Middle Eastern (MID)

AF:

0.842

AC:

239

AN:

284

European-Non Finnish (NFE)

AF:

0.829

AC:

55585

AN:

67090

Other (OTH)

AF:

0.767

AC:

1590

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1239

2478

3716

4955

6194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

826

1652

2478

3304

4130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.829

Hom.:

89710

Bravo

AF:

0.720

TwinsUK

AF:

0.852

AC:

3158

ALSPAC

AF:

0.857

AC:

3304

ESP6500AA

AF:

0.485

AC:

2136

ESP6500EA

AF:

0.856

AC:

7364

ExAC

AF:

0.764

AC:

92216

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Bilateral microtia-deafness-cleft palate syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.94

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.18

.;T;T

MetaRNN

Benign

5.6e-7

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

1.3

PrimateAI

Uncertain

0.54

PROVEAN

Benign

1.0

N;.;N

REVEL

Benign

0.026

Sift

Benign

0.89

T;.;T

Sift4G

Benign

0.36

T;.;T

Polyphen

0.0

.;.;B

Vest4

0.060

MPC

0.45

ClinPred

0.0049

GERP RS

2.5

PromoterAI

-0.066

Neutral

(source)

gMVP

0.38

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over