7-27199445-C-A

Position:

• chr7-27199445-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000522.5(HOXA13):​c.633G>T​(p.Met211Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000829 in 1,613,608 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (6 hom.)
• Consequence: HOXA13 NM_000522.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.63

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008342475).
• BP6: Variant 7-27199445-C-A is Benign according to our data. Variant chr7-27199445-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 376765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000443 (647/1461320) while in subpopulation AFR AF= 0.0169 (565/33476). AF 95% confidence interval is 0.0157. There are 6 homozygotes in gnomad4_exome. There are 243 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 691 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXA13	NM_000522.5	c.633G>T	p.Met211Ile	missense_variant	1/2	ENST00000649031.1	NP_000513.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXA13	ENST00000649031.1	c.633G>T	p.Met211Ile	missense_variant	1/2		NM_000522.5	ENSP00000497112.1
HOTTIP	ENST00000421733.1	n.167+704C>A		intron_variant		5
HOTTIP	ENST00000605136.6	n.86+115C>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 692 AN: 152170 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

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: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00122 AC: 303 AN: 247510 Hom.: 4 AF XY: 0.000831 AC XY: 112 AN XY: 134758

Gnomad AFR exome AF: 0.0174

Gnomad AMR exome AF: 0.000697

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000443 AC: 647 AN: 1461320 Hom.: 6 Cov.: 33 AF XY: 0.000334 AC XY: 243 AN XY: 726994

Gnomad4 AFR exome AF: 0.0169

Gnomad4 AMR exome AF: 0.000649

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.00454 AC: 691 AN: 152288 Hom.: 2 Cov.: 32 AF XY: 0.00432 AC XY: 322 AN XY: 74468

Gnomad4 AFR AF: 0.0159

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00105 Hom.: 1

Bravo AF: 0.00509

ESP6500AA AF: 0.0143 AC: 63

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00136 AC: 165

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	.;D
MetaRNN	Benign	0.0083	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.9	.;D
REVEL	Benign	0.17
Sift	Benign	0.084	.;T
Sift4G	Benign	0.10	.;T
Polyphen		0.59	P;P
Vest4		0.57
MutPred		0.24		Loss of disorder (P = 0.0665);Loss of disorder (P = 0.0665);
MVP		0.42
ClinPred		0.046	T
GERP RS		3.1
Varity_R		0.36
gMVP		0.47

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: rs35277569; hg19: chr7-27239064;