NM_213599.3:c.1538C>T

Variant names:

• chr11-22259649-C-T
• rs281865467
• NM_213599.3:c.1538C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PM1 PM2 PP5

The NM_213599.3(ANO5):​c.1538C>T​(p.Thr513Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000568781: Published functional studies demonstrate that T513I leads to phospholipid scrambling, suggesting a gain-of-function effect (Di Zanni et al., 2017)" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 6.16
• Publications: 15 publications found

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]

ANO5 Gene-Disease associations (from GenCC):

• gnathodiaphyseal dysplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2L

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Miyoshi muscular dystrophy 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000568781: Published functional studies demonstrate that T513I leads to phospholipid scrambling, suggesting a gain-of-function effect (Di Zanni et al., 2017); SCV000645892: Experimental studies have shown that this missense change affects ANO5 function (PMID: 29124309).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_213599.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-22259649-C-T is Pathogenic according to our data. Variant chr11-22259649-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 288853.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213599.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	NM_213599.3	MANE Select	c.1538C>T	p.Thr513Ile	missense	Exon 15 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.1535C>T	p.Thr512Ile	missense	Exon 15 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.1496C>T	p.Thr499Ile	missense	Exon 14 of 21	NP_001397892.1	A0A804HL91

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	ENST00000324559.9	TSL:1 MANE Select	c.1538C>T	p.Thr513Ile	missense	Exon 15 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.1496C>T	p.Thr499Ile	missense	Exon 14 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.1493C>T	p.Thr498Ile	missense	Exon 14 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	not provided (3)
1	-	-	Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	T
Eigen	Benign	0.058
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.74	N
PhyloP100		6.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.25
Sift	Benign	0.34	T
Sift4G	Benign	0.23	T
Polyphen		0.51	P
Vest4		0.45
MutPred		0.54		Loss of catalytic residue at T513 (P = 0.0681)
MVP		0.73
MPC		0.33
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.13
gMVP		0.52
Mutation Taster		=29/71	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs281865467; hg19: chr11-22281195;