chr7-27095694-GCGA-G

Variant names:

• chr7-27095694-GCGA-G
• rs368428758
• NM_005522.5:c.216_218delTCG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_005522.5(HOXA1):​c.216_218delTCG​(p.Arg73del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0387 in 1,302,078 control chromosomes in the GnomAD database, including 824 homozygotes. 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 0.025 (61 hom., cov: 28)
  • Exomes 𝑓: 0.041 (763 hom.)
• Consequence: HOXA1 NM_005522.5 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.13

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 -10 ACMG points.

• BP6: Variant 7-27095694-GCGA-G is Benign according to our data. Variant chr7-27095694-GCGA-G is described in ClinVar as [Likely_benign]. Clinvar id is 369584.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-27095694-GCGA-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0245 (3616/147328) while in subpopulation NFE AF = 0.0351 (2314/65910). AF 95% confidence interval is 0.0339. There are 61 homozygotes in GnomAd4. There are 1742 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 61 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXA1	NM_005522.5	c.216_218delTCG	p.Arg73del	disruptive_inframe_deletion	Exon 1 of 2	ENST00000643460.2	NP_005513.2
HOXA1	NM_153620.3	c.216_218delTCG	p.Arg73del	disruptive_inframe_deletion	Exon 1 of 3		NP_705873.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXA1	ENST00000643460.2	c.216_218delTCG	p.Arg73del	disruptive_inframe_deletion	Exon 1 of 2		NM_005522.5	ENSP00000494260.2
HOXA1	ENST00000355633.5	c.216_218delTCG	p.Arg73del	disruptive_inframe_deletion	Exon 1 of 3	1		ENSP00000347851.5
HOTAIRM1	ENST00000495032.1	n.26+23_26+25delCGA		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3616 AN: 147212 Hom.: 61 Cov.: 28

Gnomad AFR AF: 0.00672

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0310

Gnomad ASJ AF: 0.0442

Gnomad EAS AF: 0.000850

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.0251

Gnomad MID AF: 0.0329

Gnomad NFE AF: 0.0351

Gnomad OTH AF: 0.0321

GnomAD2 exomes AF: 0.0301 AC: 6251 AN: 207702 AF XY: 0.0311

Gnomad AFR exome AF: 0.00627

Gnomad AMR exome AF: 0.0258

Gnomad ASJ exome AF: 0.0583

Gnomad EAS exome AF: 0.00108

Gnomad FIN exome AF: 0.0291

Gnomad NFE exome AF: 0.0393

Gnomad OTH exome AF: 0.0347

GnomAD4 exome AF: 0.0405 AC: 46772 AN: 1154750 Hom.: 763 AF XY: 0.0403 AC XY: 23126 AN XY: 574534

Gnomad4 AFR exome AF: 0.00607 AC: 189 AN: 31158

Gnomad4 AMR exome AF: 0.0270 AC: 988 AN: 36632

Gnomad4 ASJ exome AF: 0.0539 AC: 1132 AN: 21002

Gnomad4 EAS exome AF: 0.000882 AC: 27 AN: 30604

Gnomad4 SAS exome AF: 0.0245 AC: 1617 AN: 66118

Gnomad4 FIN exome AF: 0.0316 AC: 1379 AN: 43580

Gnomad4 NFE exome AF: 0.0451 AC: 39365 AN: 872494

Gnomad4 Remaining exome AF: 0.0380 AC: 1842 AN: 48438

GnomAD4 genome AF: 0.0245 AC: 3616 AN: 147328 Hom.: 61 Cov.: 28 AF XY: 0.0243 AC XY: 1742 AN XY: 71826

Gnomad4 AFR AF: 0.00670 AC: 0.00669522 AN: 0.00669522

Gnomad4 AMR AF: 0.0309 AC: 0.0309091 AN: 0.0309091

Gnomad4 ASJ AF: 0.0442 AC: 0.0441527 AN: 0.0441527

Gnomad4 EAS AF: 0.000852 AC: 0.000851789 AN: 0.000851789

Gnomad4 SAS AF: 0.0198 AC: 0.0197802 AN: 0.0197802

Gnomad4 FIN AF: 0.0251 AC: 0.0251087 AN: 0.0251087

Gnomad4 NFE AF: 0.0351 AC: 0.0351085 AN: 0.0351085

Gnomad4 OTH AF: 0.0318 AC: 0.0317693 AN: 0.0317693

Alfa AF: 0.0248 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bilateral microtia-deafness-cleft palate syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=89/11	polymorphism (auto)

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

Publications

LitVar

Other links and lift over

dbSNP: rs368428758; hg19: chr7-27135313; COSMIC: COSV56065079; COSMIC: COSV56065079;