chr7-27095697-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7

The NM_005522.5(HOXA1):​c.216T>C​(p.His72His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 949,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000042 ( 0 hom., cov: 30)
Exomes š‘“: 0.00014 ( 0 hom. )

Consequence

HOXA1
NM_005522.5 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.358
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.63).
BP6
Variant 7-27095697-A-G is Benign according to our data. Variant chr7-27095697-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 359965.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BP7
Synonymous conserved (PhyloP=-0.358 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HOXA1NM_005522.5 linkc.216T>C p.His72His synonymous_variant Exon 1 of 2 ENST00000643460.2 NP_005513.2 P49639
HOXA1NM_153620.3 linkc.216T>C p.His72His synonymous_variant Exon 1 of 3 NP_705873.3 P49639

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HOXA1ENST00000643460.2 linkc.216T>C p.His72His synonymous_variant Exon 1 of 2 NM_005522.5 ENSP00000494260.2 A0A2R8Y4R9
HOXA1ENST00000355633.5 linkc.216T>C p.His72His synonymous_variant Exon 1 of 3 1 ENSP00000347851.5 E7ERT8
HOTAIRM1ENST00000495032.1 linkn.26+25A>G intron_variant Intron 1 of 1 5

Frequencies

GnomAD3 genomes
AF:
0.0000424
AC:
6
AN:
141484
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000249
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000799
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.000140
AC:
113
AN:
808070
Hom.:
0
Cov.:
38
AF XY:
0.000162
AC XY:
63
AN XY:
388578
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000609
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000526
Gnomad4 SAS exome
AF:
0.000510
Gnomad4 FIN exome
AF:
0.0000489
Gnomad4 NFE exome
AF:
0.000128
Gnomad4 OTH exome
AF:
0.000124
GnomAD4 genome
AF:
0.0000424
AC:
6
AN:
141484
Hom.:
0
Cov.:
30
AF XY:
0.0000290
AC XY:
2
AN XY:
69068
show subpopulations
Gnomad4 AFR
AF:
0.0000249
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000799
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000107
Hom.:
0

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Human HOXA1 syndromes Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
Mar 09, 2018
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely 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
BayesDel_noAF
Benign
-0.63
CADD
Benign
5.9
DANN
Benign
0.77

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.

Other links and lift over

dbSNP: rs886062260; hg19: chr7-27135316; API