7-27198363-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000522.5(HOXA13):c.1002A>G(p.Leu334=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 1,614,234 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (15 hom.)
• Consequence: HOXA13 NM_000522.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.57

Genes affected

HOXA13 (HGNC:5102): (homeobox A13) 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. Expansion of a polyalanine tract in the encoded protein can cause hand-foot-uterus syndrome, also known as hand-foot-genital syndrome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 7-27198363-T-C is Benign according to our data. Variant chr7-27198363-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 713824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-27198363-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.57 with no splicing effect.
• BS2: High AC in GnomAd at 317 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXA13	NM_000522.5	c.1002A>G	p.Leu334=	synonymous_variant	2/2	ENST00000649031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXA13	ENST00000649031.1	c.1002A>G	p.Leu334=	synonymous_variant	2/2		NM_000522.5	P1

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 317 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00326

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00182 AC: 458 AN: 251476 Hom.: 1 AF XY: 0.00175 AC XY: 238 AN XY: 135916

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00291

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00315 AC: 4601 AN: 1461884 Hom.: 15 Cov.: 31 AF XY: 0.00302 AC XY: 2195 AN XY: 727242

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.00137

Gnomad4 NFE exome AF: 0.00371

Gnomad4 OTH exome AF: 0.00321

GnomAD4 genome AF: 0.00208 AC: 317 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.00226 AC XY: 168 AN XY: 74498

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00326

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00265 Hom.: 0

Bravo AF: 0.00194

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00344

EpiControl AF: 0.00338

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	HOXA13: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	8.7
Dann	Benign	0.66

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: rs35608915; hg19: chr7-27237982; COSMIC: COSV56083465; COSMIC: COSV56083465;