7-27095697-A-ATGGTGG

Position:

• chr7-27095697-A-ATGGTGG

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_005522.5(HOXA1):​c.210_215dupCCACCA​(p.His71_His72dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000635 in 949,664 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00070 (1 hom.)
• Consequence: HOXA1 NM_005522.5 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.59

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 7-27095697-A-ATGGTGG is Benign according to our data. Variant chr7-27095697-A-ATGGTGG is described in ClinVar as [Likely_benign]. Clinvar id is 588681.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXA1	NM_005522.5	c.210_215dupCCACCA	p.His71_His72dup	disruptive_inframe_insertion	1/2	ENST00000643460.2	NP_005513.2
HOXA1	NM_153620.3	c.210_215dupCCACCA	p.His71_His72dup	disruptive_inframe_insertion	1/3		NP_705873.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXA1	ENST00000643460.2	c.210_215dupCCACCA	p.His71_His72dup	disruptive_inframe_insertion	1/2		NM_005522.5	ENSP00000494260.2
HOXA1	ENST00000355633.5	c.210_215dupCCACCA	p.His71_His72dup	disruptive_inframe_insertion	1/3	1		ENSP00000347851.5
HOTAIRM1	ENST00000495032.1	n.26+44_26+49dupTGGTGG		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000254 AC: 36 AN: 141484 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000640

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000214

Gnomad SAS AF: 0.000705

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000320

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000585 AC: 136 AN: 232380 Hom.: 0 AF XY: 0.000485 AC XY: 61 AN XY: 125726

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000569

Gnomad SAS exome AF: 0.000276

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000252

Gnomad OTH exome AF: 0.00123

GnomAD4 exome AF: 0.000702 AC: 567 AN: 808054 Hom.: 1 Cov.: 52 AF XY: 0.000661 AC XY: 257 AN XY: 388570

Gnomad4 AFR exome AF: 0.0000797

Gnomad4 AMR exome AF: 0.00628

Gnomad4 ASJ exome AF: 0.000166

Gnomad4 EAS exome AF: 0.00199

Gnomad4 SAS exome AF: 0.000824

Gnomad4 FIN exome AF: 0.0000979

Gnomad4 NFE exome AF: 0.000596

Gnomad4 OTH exome AF: 0.000372

GnomAD4 genome AF: 0.000254 AC: 36 AN: 141610 Hom.: 0 Cov.: 30 AF XY: 0.000231 AC XY: 16 AN XY: 69196

Gnomad4 AFR AF: 0.0000746

Gnomad4 AMR AF: 0.000639

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000215

Gnomad4 SAS AF: 0.000704

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000320

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

HOXA1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2022

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). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2018

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs747464910; hg19: chr7-27135316;