rs3757640

Positions:

• chr7-27142626-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_153631.3(HOXA3):​c.-493-2440G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 189,504 control chromosomes in the GnomAD database, including 38,591 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.61 (29690 hom., cov: 33)
  • Exomes 𝑓: 0.67 (8901 hom.)
• Consequence: HOXA3 NM_153631.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.225

Genes affected

HOXA5 (HGNC:5106): (homeobox A5) 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. Methylation of this gene may result in the loss of its expression and, since the encoded protein upregulates the tumor suppressor p53, this protein may play an important role in tumorigenesis. [provided by RefSeq, Jul 2008]

HOXA3 (HGNC:5104): (homeobox A3) 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. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

HOXA-AS3 (HGNC:43748): (HOXA cluster antisense RNA 3)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXA5	NM_019102.4	c.562+420G>A		intron_variant		ENST00000222726.4
HOXA3	NM_153631.3	c.-493-2440G>A		intron_variant		ENST00000612286.5
HOXA-AS3	NR_038832.1	n.176+2087C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXA5	ENST00000222726.4	c.562+420G>A		intron_variant		1	NM_019102.4	P1
HOXA3	ENST00000612286.5	c.-493-2440G>A		intron_variant		2	NM_153631.3	P1
HOXA-AS3	ENST00000518848.5	n.173-8949C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.607 AC: 92206 AN: 151958 Hom.: 29683 Cov.: 33

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.761

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.739

Gnomad FIN AF: 0.599

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.719

Gnomad OTH AF: 0.652

GnomAD4 exome AF: 0.675 AC: 25256 AN: 37428 Hom.: 8901 AF XY: 0.682 AC XY: 12687 AN XY: 18604

Gnomad4 AFR exome AF: 0.345

Gnomad4 AMR exome AF: 0.582

Gnomad4 ASJ exome AF: 0.732

Gnomad4 EAS exome AF: 0.620

Gnomad4 SAS exome AF: 0.728

Gnomad4 FIN exome AF: 0.585

Gnomad4 NFE exome AF: 0.707

Gnomad4 OTH exome AF: 0.640

GnomAD4 genome AF: 0.607 AC: 92241 AN: 152076 Hom.: 29690 Cov.: 33 AF XY: 0.604 AC XY: 44897 AN XY: 74324

Gnomad4 AFR AF: 0.382

Gnomad4 AMR AF: 0.627

Gnomad4 ASJ AF: 0.761

Gnomad4 EAS AF: 0.612

Gnomad4 SAS AF: 0.740

Gnomad4 FIN AF: 0.599

Gnomad4 NFE AF: 0.719

Gnomad4 OTH AF: 0.652

Alfa AF: 0.704 Hom.: 42495

Bravo AF: 0.595

Asia WGS AF: 0.645 AC: 2243 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	14
DANN	Benign	0.89

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: rs3757640; hg19: chr7-27182245;