7-27095697-ATGGTGGTGGTGG-ATGGTGGTGG

Variant names:

• chr7-27095697-ATGG-A
• rs747464910
• NM_005522.5:c.213_215delCCA

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_005522.5(HOXA1):​c.213_215delCCA​(p.His72del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 943,574 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H71H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: HOXA1 NM_005522.5 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.02
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005522.5
• BP6: Variant 7-27095697-ATGG-A is Benign according to our data. Variant chr7-27095697-ATGG-A is described in ClinVar as Likely_benign. ClinVar VariationId is 588087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005522.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA1	NM_005522.5	MANE Select	c.213_215delCCA	p.His72del	disruptive_inframe_deletion	Exon 1 of 2	NP_005513.2	P49639-1
	HOXA1	NM_153620.3		c.213_215delCCA	p.His72del	disruptive_inframe_deletion	Exon 1 of 3	NP_705873.3	P49639-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA1	ENST00000643460.2	MANE Select	c.213_215delCCA	p.His72del	disruptive_inframe_deletion	Exon 1 of 2	ENSP00000494260.2	P49639-1
	HOXA1	ENST00000355633.5	TSL:1	c.213_215delCCA	p.His72del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000347851.5	E7ERT8
	HOTAIRM1	ENST00000495032.1	TSL:5	n.26+47_26+49delTGG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 170 AN: 141466 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00192

Gnomad ASJ AF: 0.00127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000940

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000639

Gnomad OTH AF: 0.00207

GnomAD2 exomes AF: 0.000783 AC: 182 AN: 232380 AF XY: 0.000803

Gnomad AFR exome AF: 0.00263

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.000549

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000101

Gnomad NFE exome AF: 0.000736

Gnomad OTH exome AF: 0.000701

GnomAD4 exome AF: 0.00110 AC: 885 AN: 801982 Hom.: 2 AF XY: 0.00118 AC XY: 454 AN XY: 385670

African (AFR) AF: 0.00235 AC: 58 AN: 24636

American (AMR) AF: 0.00331 AC: 54 AN: 16326

Ashkenazi Jewish (ASJ) AF: 0.000835 AC: 10 AN: 11972

East Asian (EAS) AF: 0.00 AC: 0 AN: 17092

South Asian (SAS) AF: 0.00189 AC: 48 AN: 25436

European-Finnish (FIN) AF: 0.000297 AC: 6 AN: 20182

Middle Eastern (MID) AF: 0.00177 AC: 6 AN: 3388

European-Non Finnish (NFE) AF: 0.00102 AC: 667 AN: 650954

Other (OTH) AF: 0.00113 AC: 36 AN: 31996

GnomAD4 genome AF: 0.00121 AC: 171 AN: 141592 Hom.: 0 Cov.: 30 AF XY: 0.00129 AC XY: 89 AN XY: 69190

African (AFR) AF: 0.00226 AC: 91 AN: 40222

American (AMR) AF: 0.00192 AC: 27 AN: 14084

Ashkenazi Jewish (ASJ) AF: 0.00127 AC: 4 AN: 3162

East Asian (EAS) AF: 0.00 AC: 0 AN: 4656

South Asian (SAS) AF: 0.000938 AC: 4 AN: 4264

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.000655 AC: 41 AN: 62548

Other (OTH) AF: 0.00205 AC: 4 AN: 1948

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00126

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs747464910; hg19: chr7-27135316; COSMIC: COSV56065953; COSMIC: COSV56065953;