rs200553437

chr11-22250352-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_213599.3(ANO5):c.994A>G(p.Met332Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000291 in 1,613,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M332I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.82

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 Likely_benign. Variant got -4 ACMG points.

• PM1: In a topological_domain Extracellular (size 59) in uniprot entity ANO5_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_213599.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.07073429).
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO5	NM_213599.3	c.994A>G	p.Met332Val	missense_variant	10/22	ENST00000324559.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO5	ENST00000324559.9	c.994A>G	p.Met332Val	missense_variant	10/22	1	NM_213599.3	P2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 250756 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

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: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461270 Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15 AN XY: 726930

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74450

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.000310

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 30, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 09, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	ANO5: PM2, BP4 -

Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 332 of the ANO5 protein (p.Met332Val). This variant is present in population databases (rs200553437, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ANO5-related conditions. ClinVar contains an entry for this variant (Variation ID: 468848). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ANO5 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	17
Dann	Benign	0.82
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.80	D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.066
Sift	Benign	0.089	T
Sift4G	Benign	0.34	T
Polyphen		0.025	B
Vest4		0.21
MVP		0.37
MPC		0.091
ClinPred		0.17	T
GERP RS		4.3
Varity_R		0.15
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200553437; hg19: chr11-22271898; COSMIC: COSV100201350;