7-27095697-ATGGTGGTGG-A

Position:

• chr7-27095697-ATGGTGGTGG-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_005522.5(HOXA1):​c.207_215del​(p.His70_His72del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00329 in 949,682 control chromosomes in the GnomAD database, including 25 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (3 hom., cov: 30)
  • Exomes 𝑓: 0.0035 (22 hom.)
• Consequence: HOXA1 NM_005522.5 inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.23

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 7-27095697-ATGGTGGTGG-A is Benign according to our data. Variant chr7-27095697-ATGGTGGTGG-A is described in ClinVar as [Benign]. Clinvar id is 587887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-27095697-ATGGTGGTGG-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00354 (2864/808074) while in subpopulation SAS AF= 0.0485 (1238/25506). AF 95% confidence interval is 0.0463. There are 22 homozygotes in gnomad4_exome. There are 1658 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXA1	NM_005522.5	c.207_215del	p.His70_His72del	inframe_deletion	1/2	ENST00000643460.2	NP_005513.2
HOXA1	NM_153620.3	c.207_215del	p.His70_His72del	inframe_deletion	1/3		NP_705873.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXA1	ENST00000643460.2	c.207_215del	p.His70_His72del	inframe_deletion	1/2		NM_005522.5	ENSP00000494260	P1
HOXA1	ENST00000355633.5	c.207_215del	p.His70_His72del	inframe_deletion	1/3	1		ENSP00000347851
HOTAIRM1	ENST00000495032.1	n.26+41_26+49del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 260 AN: 141482 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.000424

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00348

Gnomad ASJ AF: 0.0180

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0136

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0207

Gnomad NFE AF: 0.00102

Gnomad OTH AF: 0.00467

GnomAD3 exomes AF: 0.00364 AC: 846 AN: 232380 Hom.: 11 AF XY: 0.00408 AC XY: 513 AN XY: 125726

Gnomad AFR exome AF: 0.000514

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.0000569

Gnomad SAS exome AF: 0.0161

Gnomad FIN exome AF: 0.0000507

Gnomad NFE exome AF: 0.00139

Gnomad OTH exome AF: 0.00491

GnomAD4 exome AF: 0.00354 AC: 2864 AN: 808074 Hom.: 22 AF XY: 0.00427 AC XY: 1658 AN XY: 388582

Gnomad4 AFR exome AF: 0.000916

Gnomad4 AMR exome AF: 0.00524

Gnomad4 ASJ exome AF: 0.0268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0485

Gnomad4 FIN exome AF: 0.0000979

Gnomad4 NFE exome AF: 0.00140

Gnomad4 OTH exome AF: 0.00633

GnomAD4 genome AF: 0.00183 AC: 259 AN: 141608 Hom.: 3 Cov.: 30 AF XY: 0.00223 AC XY: 154 AN XY: 69194

Gnomad4 AFR AF: 0.000423

Gnomad4 AMR AF: 0.00348

Gnomad4 ASJ AF: 0.0180

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0134

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00102

Gnomad4 OTH AF: 0.00462

Bravo AF: 0.00170

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2018

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

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;