chr7-27199462-A-AGGC

Variant names:

• chr7-27199462-A-AGGC
• rs750672289
• NM_000522.5:c.613_615dupGCC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.01
• Publications: 1 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -17 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 Benign/Likely_benign. ClinVar VariationId is 2052430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 passed quality control check.
• BS2: High AC in GnomAd4 at 59 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000522.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA13	NM_000522.5	MANE Select	c.613_615dupGCC	p.Ala205dup	conservative_inframe_insertion	Exon 1 of 2	NP_000513.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA13	ENST00000649031.1	MANE Select	c.613_615dupGCC	p.Ala205dup	conservative_inframe_insertion	Exon 1 of 2	ENSP00000497112.1	P31271
	HOTTIP	ENST00000421733.1	TSL:5	n.167+737_167+739dupGGC		intron	N/A
	HOTTIP	ENST00000605136.7	TSL:2	n.92+148_92+150dupGGC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 151906 Hom.: 0 Cov.: 32

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: 66 AN: 242272 AF XY: 0.000309

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.: 2 Cov.: 33 AF XY: 0.000434 AC XY: 315 AN XY: 726550

African (AFR) AF: 0.0000598 AC: 2 AN: 33462

American (AMR) AF: 0.000895 AC: 40 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000513 AC: 570 AN: 1111646

Other (OTH) AF: 0.000464 AC: 28 AN: 60300

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152022 Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74334

African (AFR) AF: 0.000217 AC: 9 AN: 41502

American (AMR) AF: 0.00164 AC: 25 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 67928

Other (OTH) AF: 0.000476 AC: 1 AN: 2102

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000366

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital heart disease (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=71/29	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs750672289; hg19: chr7-27239081;