7-27199656-G-GGGCCCGCCT

Position:

• chr7-27199656-G-GGGCCCGCCT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM4 BP6_Moderate BS1 BS2

The NM_000522.5(HOXA13):​c.421_422insAGGCGGGCC​(p.Gly140_Pro141insGlnAlaGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000539 in 1,252,972 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: HOXA13 NM_000522.5 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 0.0860

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

Verdict is Benign. Variant got -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000522.5.
• BP6: Variant 7-27199656-G-GGGCCCGCCT is Benign according to our data. Variant chr7-27199656-G-GGGCCCGCCT is described in ClinVar as [Benign]. Clinvar id is 592017.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00278 (409/146974) while in subpopulation AFR AF= 0.00971 (395/40696). AF 95% confidence interval is 0.00892. There are 4 homozygotes in gnomad4. There are 189 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 409 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXA13	NM_000522.5	c.421_422insAGGCGGGCC	p.Gly140_Pro141insGlnAlaGly	conservative_inframe_insertion	1/2	ENST00000649031.1	NP_000513.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXA13	ENST00000649031.1	c.421_422insAGGCGGGCC	p.Gly140_Pro141insGlnAlaGly	conservative_inframe_insertion	1/2		NM_000522.5	ENSP00000497112.1
HOTTIP	ENST00000421733.1	n.167+919_167+920insCGCCTGGCC		intron_variant		5
HOTTIP	ENST00000605136.6	n.86+330_86+331insCGCCTGGCC		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00278 AC: 409 AN: 146874 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00973

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000875

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: 0.00

Gnomad OTH AF: 0.000498

GnomAD4 exome AF: 0.000241 AC: 266 AN: 1105998 Hom.: 2 Cov.: 32 AF XY: 0.000203 AC XY: 107 AN XY: 526934

Gnomad4 AFR exome AF: 0.0112

Gnomad4 AMR exome AF: 0.000253

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000107

Gnomad4 OTH exome AF: 0.000316

GnomAD4 genome AF: 0.00278 AC: 409 AN: 146974 Hom.: 4 Cov.: 31 AF XY: 0.00264 AC XY: 189 AN XY: 71692

Gnomad4 AFR AF: 0.00971

Gnomad4 AMR AF: 0.000874

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000492

Alfa AF: 0.00253 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs35599078; hg19: chr7-27239275;