rs34957925

Positions:

• chr7-27171929-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_018951.4(HOXA10):​c.1203G>A​(p.Arg401=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.034 in 1,614,060 control chromosomes in the GnomAD database, including 1,102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.025 (73 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1029 hom.)
• Consequence: HOXA10 NM_018951.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0840

Genes affected

HOXA10 (HGNC:5100): (homeobox A10) 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 that may regulate gene expression, morphogenesis, and differentiation. More specifically, it may function in fertility, embryo viability, and regulation of hematopoietic lineage commitment. Alternatively spliced transcript variants have been described. Read-through transcription also exists between this gene and the downstream homeobox A9 (HOXA9) gene. [provided by RefSeq, Mar 2011]

HOXA9 (HGNC:5109): (homeobox A9) 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. This gene is highly similar to the abdominal-B (Abd-B) gene of Drosophila. A specific translocation event which causes a fusion between this gene and the NUP98 gene has been associated with myeloid leukemogenesis. Read-through transcription exists between this gene and the upstream homeobox A10 (HOXA10) gene.[provided by RefSeq, Mar 2011]

HOXA10-HOXA9 (HGNC:):

HOXA10-AS (HGNC:40281): (HOXA10 antisense RNA)

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 7-27171929-C-T is Benign according to our data. Variant chr7-27171929-C-T is described in ClinVar as [Benign]. Clinvar id is 3056353.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.084 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0251 (3823/152248) while in subpopulation NFE AF= 0.0394 (2677/68018). AF 95% confidence interval is 0.0381. There are 73 homozygotes in gnomad4. There are 1848 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3823 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXA10	NM_018951.4	c.1203G>A	p.Arg401=	synonymous_variant	2/2	ENST00000283921.5
HOXA10-HOXA9	NR_037940.1	n.617-6962G>A		intron_variant, non_coding_transcript_variant
HOXA10	NR_037939.2	n.461G>A		non_coding_transcript_exon_variant	2/2
HOXA10-AS	NR_046609.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXA10	ENST00000283921.5	c.1203G>A	p.Arg401=	synonymous_variant	2/2	1	NM_018951.4	P2
HOXA10-AS	ENST00000519935.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3822 AN: 152130 Hom.: 72 Cov.: 33

Gnomad AFR AF: 0.00705

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.0210

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0350

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0393

Gnomad OTH AF: 0.0282

GnomAD3 exomes AF: 0.0258 AC: 6490 AN: 251488 Hom.: 131 AF XY: 0.0266 AC XY: 3610 AN XY: 135920

Gnomad AFR exome AF: 0.00689

Gnomad AMR exome AF: 0.0157

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00647

Gnomad FIN exome AF: 0.0294

Gnomad NFE exome AF: 0.0411

Gnomad OTH exome AF: 0.0275

GnomAD4 exome AF: 0.0349 AC: 51038 AN: 1461812 Hom.: 1029 Cov.: 32 AF XY: 0.0344 AC XY: 25008 AN XY: 727224

Gnomad4 AFR exome AF: 0.00535

Gnomad4 AMR exome AF: 0.0166

Gnomad4 ASJ exome AF: 0.0150

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00769

Gnomad4 FIN exome AF: 0.0298

Gnomad4 NFE exome AF: 0.0410

Gnomad4 OTH exome AF: 0.0292

GnomAD4 genome AF: 0.0251 AC: 3823 AN: 152248 Hom.: 73 Cov.: 33 AF XY: 0.0248 AC XY: 1848 AN XY: 74440

Gnomad4 AFR AF: 0.00703

Gnomad4 AMR AF: 0.0210

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00643

Gnomad4 FIN AF: 0.0350

Gnomad4 NFE AF: 0.0394

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0322 Hom.: 38

Bravo AF: 0.0242

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0385

EpiControl AF: 0.0437

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HOXA10-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
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: rs34957925; hg19: chr7-27211548;