rs199620262

Variant names:

• chr7-27095703-G-A
• rs199620262
• NM_005522.5:c.210C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_005522.5(HOXA1):​c.210C>T​(p.His70His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000536 in 1,567,694 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00054 (4 hom.)
• Consequence: HOXA1 NM_005522.5 synonymous
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.78

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP7: Synonymous conserved (PhyloP=1.78 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXA1	NM_005522.5	c.210C>T	p.His70His	synonymous_variant	Exon 1 of 2	ENST00000643460.2	NP_005513.2
HOXA1	NM_153620.3	c.210C>T	p.His70His	synonymous_variant	Exon 1 of 3		NP_705873.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXA1	ENST00000643460.2	c.210C>T	p.His70His	synonymous_variant	Exon 1 of 2		NM_005522.5	ENSP00000494260.2
HOXA1	ENST00000355633.5	c.210C>T	p.His70His	synonymous_variant	Exon 1 of 3	1		ENSP00000347851.5
HOTAIRM1	ENST00000495032.1	n.26+31G>A		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.000462 AC: 70 AN: 151394 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.000297

Gnomad EAS AF: 0.00194

Gnomad SAS AF: 0.00170

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000483

GnomAD3 exomes AF: 0.000628 AC: 156 AN: 248326 Hom.: 1 AF XY: 0.000781 AC XY: 105 AN XY: 134502

Gnomad AFR exome AF: 0.000619

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00185

Gnomad SAS exome AF: 0.00194

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000332

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.000544 AC: 771 AN: 1416180 Hom.: 4 Cov.: 38 AF XY: 0.000588 AC XY: 413 AN XY: 702634

Gnomad4 AFR exome AF: 0.000514

Gnomad4 AMR exome AF: 0.000235

Gnomad4 ASJ exome AF: 0.000122

Gnomad4 EAS exome AF: 0.00388

Gnomad4 SAS exome AF: 0.00259

Gnomad4 FIN exome AF: 0.0000195

Gnomad4 NFE exome AF: 0.000322

Gnomad4 OTH exome AF: 0.000567

GnomAD4 genome AF: 0.000462 AC: 70 AN: 151514 Hom.: 0 Cov.: 30 AF XY: 0.000513 AC XY: 38 AN XY: 74002

Gnomad4 AFR AF: 0.000531

Gnomad4 AMR AF: 0.000198

Gnomad4 ASJ AF: 0.000297

Gnomad4 EAS AF: 0.00194

Gnomad4 SAS AF: 0.00170

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000369

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000240 Hom.: 0

EpiCase AF: 0.000273

EpiControl AF: 0.000475

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Human HOXA1 syndromes Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	6.0
DANN	Benign	0.94

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: rs199620262; hg19: chr7-27135322;