7-27095697-ATGGTGGTGGTGG-ATGGTGGTGGTGGTGG

Variant names:

• chr7-27095697-A-ATGG
• rs747464910
• NM_005522.5:c.213_215dupCCA

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.213_215dupCCA​(p.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 0.00465 in 949,602 control chromosomes in the GnomAD database, including 35 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (17 hom., cov: 30)
  • Exomes 𝑓: 0.0040 (18 hom.)
• Consequence: HOXA1 NM_005522.5 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts 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 Benign. Variant got -16 ACMG points.

• BP6: Variant 7-27095697-A-ATGG is Benign according to our data. Variant chr7-27095697-A-ATGG is described in ClinVar as [Likely_benign]. Clinvar id is 587851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00816 (1156/141604) while in subpopulation AFR AF= 0.023 (925/40226). AF 95% confidence interval is 0.0218. There are 17 homozygotes in gnomad4. There are 544 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXA1	NM_005522.5	c.213_215dupCCA	p.His72dup	disruptive_inframe_insertion	Exon 1 of 2	ENST00000643460.2	NP_005513.2
HOXA1	NM_153620.3	c.213_215dupCCA	p.His72dup	disruptive_inframe_insertion	Exon 1 of 3		NP_705873.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXA1	ENST00000643460.2	c.213_215dupCCA	p.His72dup	disruptive_inframe_insertion	Exon 1 of 2		NM_005522.5	ENSP00000494260.2
HOXA1	ENST00000355633.5	c.213_215dupCCA	p.His72dup	disruptive_inframe_insertion	Exon 1 of 3	1		ENSP00000347851.5
HOTAIRM1	ENST00000495032.1	n.26+47_26+49dupTGG		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.00819 AC: 1158 AN: 141478 Hom.: 17 Cov.: 30

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00391

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0157

Gnomad SAS AF: 0.00446

Gnomad FIN AF: 0.000838

Gnomad MID AF: 0.00690

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00571

GnomAD3 exomes AF: 0.00386 AC: 897 AN: 232380 Hom.: 5 AF XY: 0.00340 AC XY: 427 AN XY: 125726

Gnomad AFR exome AF: 0.0230

Gnomad AMR exome AF: 0.00277

Gnomad ASJ exome AF: 0.000110

Gnomad EAS exome AF: 0.0136

Gnomad SAS exome AF: 0.00331

Gnomad FIN exome AF: 0.000304

Gnomad NFE exome AF: 0.000901

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00404 AC: 3263 AN: 807998 Hom.: 18 Cov.: 52 AF XY: 0.00410 AC XY: 1593 AN XY: 388544

Gnomad4 AFR exome AF: 0.0290

Gnomad4 AMR exome AF: 0.00755

Gnomad4 ASJ exome AF: 0.000166

Gnomad4 EAS exome AF: 0.0398

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.00127

Gnomad4 NFE exome AF: 0.00180

Gnomad4 OTH exome AF: 0.00655

GnomAD4 genome AF: 0.00816 AC: 1156 AN: 141604 Hom.: 17 Cov.: 30 AF XY: 0.00786 AC XY: 544 AN XY: 69192

Gnomad4 AFR AF: 0.0230

Gnomad4 AMR AF: 0.00391

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0159

Gnomad4 SAS AF: 0.00446

Gnomad4 FIN AF: 0.000838

Gnomad4 NFE AF: 0.000991

Gnomad4 OTH AF: 0.00565

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Jun 21, 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. -

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;