11-22250927-A-T

Position:

• chr11-22250927-A-T

Variant summary

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

The NM_213599.3(ANO5):​c.1120-24A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0297 in 1,609,586 control chromosomes in the GnomAD database, including 886 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.021 (50 hom., cov: 32)
  • Exomes 𝑓: 0.031 (836 hom.)
• Consequence: ANO5 NM_213599.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.386

Genes affected

ANO5 (HGNC:27337): (anoctamin 5) This gene encodes a member of the anoctamin family of transmembrane proteins. The encoded protein is likely a calcium activated chloride channel. Mutations in this gene have been associated with gnathodiaphyseal dysplasia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 2 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-22250927-A-T is Benign according to our data. Variant chr11-22250927-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 263308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0206 (3138/152140) while in subpopulation NFE AF= 0.0339 (2306/67984). AF 95% confidence interval is 0.0328. There are 50 homozygotes in gnomad4. There are 1457 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3138 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO5	NM_213599.3	c.1120-24A>T		intron_variant		ENST00000324559.9	NP_998764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9	c.1120-24A>T		intron_variant		1	NM_213599.3	ENSP00000315371	P2

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3138 AN: 152022 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.00727

Gnomad AMI AF: 0.0703

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0240

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0339

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.0190 AC: 4758 AN: 250078 Hom.: 72 AF XY: 0.0189 AC XY: 2559 AN XY: 135214

Gnomad AFR exome AF: 0.00610

Gnomad AMR exome AF: 0.00736

Gnomad ASJ exome AF: 0.00677

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.0245

Gnomad NFE exome AF: 0.0323

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0307 AC: 44685 AN: 1457446 Hom.: 836 Cov.: 32 AF XY: 0.0294 AC XY: 21296 AN XY: 725336

Gnomad4 AFR exome AF: 0.00536

Gnomad4 AMR exome AF: 0.00812

Gnomad4 ASJ exome AF: 0.00571

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00157

Gnomad4 FIN exome AF: 0.0258

Gnomad4 NFE exome AF: 0.0369

Gnomad4 OTH exome AF: 0.0266

GnomAD4 genome AF: 0.0206 AC: 3138 AN: 152140 Hom.: 50 Cov.: 32 AF XY: 0.0196 AC XY: 1457 AN XY: 74388

Gnomad4 AFR AF: 0.00725

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0240

Gnomad4 NFE AF: 0.0339

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.0141 Hom.: 9

Bravo AF: 0.0195

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Miyoshi muscular dystrophy 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Gnathodiaphyseal dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Autosomal recessive limb-girdle muscular dystrophy type 2L Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.56
La Branchor		0.48
BranchPoint Hunter		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs11026476; hg19: chr11-22272473;