rs35599078

Variant names:

• chr7-27199656-G-GGGCCCGCCT
• rs35599078
• NM_000522.5:c.421_422insAGGCGGGCC

Variant summary

Our verdict is Benign. The variant received -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 (★). Synonymous variant affecting the same amino acid position (i.e. P141P) has been classified as Likely 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
• 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 409 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXA13	NM_000522.5	c.421_422insAGGCGGGCC	p.Gly140_Pro141insGlnAlaGly	conservative_inframe_insertion	Exon 1 of 2	ENST00000649031.1	NP_000513.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXA13	ENST00000649031.1	c.421_422insAGGCGGGCC	p.Gly140_Pro141insGlnAlaGly	conservative_inframe_insertion	Exon 1 of 2		NM_000522.5	ENSP00000497112.1
HOTTIP	ENST00000421733.1	n.167+919_167+920insCGCCTGGCC		intron_variant	Intron 1 of 1	5
HOTTIP	ENST00000605136.7	n.92+330_92+331insCGCCTGGCC		intron_variant	Intron 1 of 1	2
HOTTIP	ENST00000814985.1	n.229+483_229+484insCGCCTGGCC		intron_variant	Intron 1 of 1

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

African (AFR) AF: 0.0112 AC: 249 AN: 22322

American (AMR) AF: 0.000253 AC: 2 AN: 7900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14164

East Asian (EAS) AF: 0.00 AC: 0 AN: 25138

South Asian (SAS) AF: 0.00 AC: 0 AN: 28480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2978

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 937706

Other (OTH) AF: 0.000316 AC: 14 AN: 44276

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

African (AFR) AF: 0.00971 AC: 395 AN: 40696

American (AMR) AF: 0.000874 AC: 13 AN: 14882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3386

East Asian (EAS) AF: 0.00 AC: 0 AN: 4970

South Asian (SAS) AF: 0.00 AC: 0 AN: 4754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66066

Other (OTH) AF: 0.000492 AC: 1 AN: 2034

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

Nov 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.086
Mutation Taster		=70/30	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs35599078; hg19: chr7-27239275;