7-27173482-G-C

Position:

• chr7-27173482-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_018951.4(HOXA10):​c.825C>G​(p.Pro275=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000924 in 1,554,794 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00089 (2 hom.)
• Consequence: HOXA10 NM_018951.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0820

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:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007973731).
• BP6: Variant 7-27173482-G-C is Benign according to our data. Variant chr7-27173482-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3042964.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.082 with no splicing effect.
• BS2: High AC in GnomAd4 at 187 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXA10	NM_018951.4	c.825C>G	p.Pro275=	synonymous_variant	1/2	ENST00000283921.5
HOXA10-HOXA9	NR_037940.1	n.616+6164C>G		intron_variant, non_coding_transcript_variant
HOXA10	NR_037939.2	n.217-1309C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXA10	ENST00000283921.5	c.825C>G	p.Pro275=	synonymous_variant	1/2	1	NM_018951.4	P2
HOXA10	ENST00000396344.4	c.11-1309C>G		intron_variant		1		A1
HOXA9	ENST00000465941.1	n.479+1220C>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152136 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000918 AC: 140 AN: 152510 Hom.: 0 AF XY: 0.000806 AC XY: 69 AN XY: 85642

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000567

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000782

Gnomad OTH exome AF: 0.000759

GnomAD4 exome AF: 0.000891 AC: 1249 AN: 1402548 Hom.: 2 Cov.: 33 AF XY: 0.000895 AC XY: 622 AN XY: 694612

Gnomad4 AFR exome AF: 0.0000654

Gnomad4 AMR exome AF: 0.00260

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.0000272

Gnomad4 SAS exome AF: 0.000947

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000872

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152246 Hom.: 2 Cov.: 33 AF XY: 0.00126 AC XY: 94 AN XY: 74442

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00135

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.00131

ExAC AF: 0.000649 AC: 63

Asia WGS AF: 0.000868 AC: 4 AN: 3470

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HOXA10-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2019

This variant is classified as likely 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_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.2
DANN	Benign	0.78
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D;D
Sift4G	Benign	0.55	T
Vest4		0.20
MVP		0.49
ClinPred		0.023	T
GERP RS		0.49

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: rs576560374; hg19: chr7-27213101;