chr7-27095697-A-ATGGTGGTGG

Variant names:

• chr7-27095697-A-ATGGTGGTGG
• rs747464910
• NM_005522.5:c.207_215dupCCACCACCA

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP3 BP6_Moderate

The NM_005522.5(HOXA1):​c.207_215dupCCACCACCA​(p.His70_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 0.000304 in 141,610 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. H72H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00067 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: HOXA1 NM_005522.5 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.59
• 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: Likely_benign. The variant received -3 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005522.5
• BP6: Variant 7-27095697-A-ATGGTGGTGG is Benign according to our data. Variant chr7-27095697-A-ATGGTGGTGG is described in ClinVar as Likely_benign. ClinVar VariationId is 587896.Status of the report is criteria_provided_single_submitter, 1 stars.

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.207_215dupCCACCACCA	p.His70_His72dup	disruptive_inframe_insertion	Exon 1 of 2	NP_005513.2	P49639-1
	HOXA1	NM_153620.3		c.207_215dupCCACCACCA	p.His70_His72dup	disruptive_inframe_insertion	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.207_215dupCCACCACCA	p.His70_His72dup	disruptive_inframe_insertion	Exon 1 of 2	ENSP00000494260.2	P49639-1
	HOXA1	ENST00000355633.5	TSL:1	c.207_215dupCCACCACCA	p.His70_His72dup	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000347851.5	E7ERT8
	HOTAIRM1	ENST00000495032.1	TSL:5	n.26+41_26+49dupTGGTGGTGG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000304 AC: 43 AN: 141484 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000997

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000711

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00846

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000320

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000818 AC: 190 AN: 232380 AF XY: 0.00117

Gnomad AFR exome AF: 0.000193

Gnomad AMR exome AF: 0.0000615

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000171

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000872

Gnomad OTH exome AF: 0.000351

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000668 AC: 540 AN: 808064 Hom.: 2 Cov.: 52 AF XY: 0.00102 AC XY: 395 AN XY: 388578

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000199 AC: 5 AN: 25106

American (AMR) AF: 0.000183 AC: 3 AN: 16414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12048

East Asian (EAS) AF: 0.000292 AC: 5 AN: 17096

South Asian (SAS) AF: 0.0176 AC: 449 AN: 25504

European-Finnish (FIN) AF: 0.0000489 AC: 1 AN: 20436

Middle Eastern (MID) AF: 0.000294 AC: 1 AN: 3402

European-Non Finnish (NFE) AF: 0.0000930 AC: 61 AN: 655822

Other (OTH) AF: 0.000465 AC: 15 AN: 32236

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000304 AC: 43 AN: 141610 Hom.: 0 Cov.: 30 AF XY: 0.000448 AC XY: 31 AN XY: 69196

African (AFR) AF: 0.0000994 AC: 4 AN: 40230

American (AMR) AF: 0.0000710 AC: 1 AN: 14084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3162

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

South Asian (SAS) AF: 0.00844 AC: 36 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: 0.0000320 AC: 2 AN: 62558

Other (OTH) AF: 0.00 AC: 0 AN: 1948

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=72/28	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs747464910; hg19: chr7-27135316;