NM_015205.3:c.418C>G

Variant names:

• chr13-112810703-C-G
• rs372464773
• NM_015205.3:c.418C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_015205.3(ATP11A):​c.418C>G​(p.Arg140Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R140Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ATP11A NM_015205.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76
• Publications: 4 publications found

Genes affected

ATP11A (HGNC:13552): (ATPase phospholipid transporting 11A) The protein encoded by this gene is an integral membrane ATPase. The encoded protein is probably phosphorylated in its intermediate state and likely drives the transport of ions such as calcium across membranes. [provided by RefSeq, Apr 2022]

ATP11A Gene-Disease associations (from GenCC):

• auditory neuropathy, autosomal dominant 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• hearing loss, autosomal dominant 84

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• leukodystrophy, hypomyelinating, 24

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000303208 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 16 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015205.3. 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
	ATP11A	NM_015205.3	MANE Select	c.418C>G	p.Arg140Gly	missense	Exon 5 of 30	NP_056020.2	P98196
	ATP11A	NM_001405661.1		c.418C>G	p.Arg140Gly	missense	Exon 5 of 29	NP_001392590.1
	ATP11A	NM_032189.4		c.418C>G	p.Arg140Gly	missense	Exon 5 of 29	NP_115565.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP11A	ENST00000375645.8	TSL:5 MANE Select	c.418C>G	p.Arg140Gly	missense	Exon 5 of 30	ENSP00000364796.3	P98196
	ATP11A	ENST00000418678.5	TSL:1	c.340C>G	p.Arg114Gly	missense	Exon 4 of 23	ENSP00000396374.1	H0Y547
	ATP11A	ENST00000375630.6	TSL:5	c.418C>G	p.Arg140Gly	missense	Exon 5 of 29	ENSP00000364781.2	E9PEJ6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251402 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461808 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	2.0	M
PhyloP100		1.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.59
Sift	Benign	0.12	T
Sift4G	Benign	0.26	T
Polyphen		0.0080	B
Vest4		0.59
MutPred		0.48		Gain of catalytic residue at L138 (P = 0.0177)
MVP		0.79
MPC		0.39
ClinPred		0.69	D
GERP RS		4.8
Varity_R		0.42
gMVP		0.84
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs372464773; hg19: chr13-113465017;