Genetic Variant HOXA13:p.Ala205dup (chr7-27199462-A-AGGC) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3BP6_ModerateBS1BS2

The NM_000522.5(HOXA13):c.613_615dupGCC(p.Ala205dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00044 in 1,612,492 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 2 hom. )

Consequence

HOXA13
NM_000522.5 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.01

Variant links:

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]

HOXA13 links:

HOTTIP (HGNC:37461): (HOXA distal transcript antisense RNA) This gene produces a long RNA in antisense to the HOXA gene cluster. This transcript may regulate expression of HOXA genes in cis. This gene is upregulated in tumors and is implicated in the promotion of cell proliferation. [provided by RefSeq, Dec 2017]

HOTTIP links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_000522.5

BP6

Variant 7-27199462-A-AGGC is Benign according to our data. Variant chr7-27199462-A-AGGC is described in ClinVar as [Likely_benign]. Clinvar id is 2052430.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000388 (59/152022) while in subpopulation AMR AF = 0.00164 (25/15288). AF 95% confidence interval is 0.00114. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High AC in GnomAd4 at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXA13	NM_000522.5 link	c.613_615dupGCC	p.Ala205dup	conservative_inframe_insertion	Exon 1 of 2	ENST00000649031.1	NP_000513.2	P31271Q6DI00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HOXA13	ENST00000649031.1 link	c.613_615dupGCC	p.Ala205dup	conservative_inframe_insertion	Exon 1 of 2		NM_000522.5	ENSP00000497112.1	P31271
HOTTIP	ENST00000421733.1 link	n.167+737_167+739dupGGC		intron_variant	Intron 1 of 1	5
HOTTIP	ENST00000605136.6 link	n.86+148_86+150dupGGC		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

151906

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.000272

AC:

AN:

242272

AF XY:

0.000309

show subpopulations

Gnomad AFR exome

AF:

0.000203

Gnomad AMR exome

AF:

0.000846

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000259

Gnomad OTH exome

AF:

0.000847

GnomAD4 exome

AF:

0.000446

AC:

651

AN:

1460470

Hom.:

Cov.:

AF XY:

0.000434

AC XY:

315

AN XY:

726550

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

AC:

AN:

33462

Gnomad4 AMR exome

AF:

0.000895

AC:

AN:

44700

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26106

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39694

Gnomad4 SAS exome

AF:

0.000128

AC:

AN:

86246

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

52554

Gnomad4 NFE exome

AF:

0.000513

AC:

570

AN:

1111646

Gnomad4 Remaining exome

AF:

0.000464

AC:

AN:

60300

Heterozygous variant carriers

117

156

195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000388

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.000217

AC:

0.000216857

AN:

0.000216857

Gnomad4 AMR

AF:

0.00164

AC:

0.00163527

AN:

0.00163527

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000353

AC:

0.000353315

AN:

0.000353315

Gnomad4 OTH

AF:

0.000476

AC:

0.000475737

AN:

0.000475737

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.000366

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=71/29

polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over