NM_012463.4:c.-170C>A

Variant names:

• chr12-123712396-C-A
• rs540324717
• NM_012463.4:c.-170C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_012463.4(ATP6V0A2):​c.-170C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000688 in 372,246 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (1 hom.)
• Consequence: ATP6V0A2 NM_012463.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.144
• Publications: 0 publications found

Genes affected

ATP6V0A2 (HGNC:18481): (ATPase H+ transporting V0 subunit a2) The protein encoded by this gene is a subunit of the vacuolar ATPase (v-ATPase), an heteromultimeric enzyme that is present in intracellular vesicles and in the plasma membrane of specialized cells, and which is essential for the acidification of diverse cellular components. V-ATPase is comprised of a membrane peripheral V(1) domain for ATP hydrolysis, and an integral membrane V(0) domain for proton translocation. The subunit encoded by this gene is a component of the V(0) domain. Mutations in this gene are a cause of both cutis laxa type II and wrinkly skin syndrome. [provided by RefSeq, Jul 2009]

ATP6V0A2 Gene-Disease associations (from GenCC):

• autosomal recessive cutis laxa type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• wrinkly skin syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
• autosomal recessive cutis laxa type 2, classic type

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000506 (77/152110) while in subpopulation NFE AF = 0.000986 (67/67948). AF 95% confidence interval is 0.000796. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012463.4. 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
	ATP6V0A2	NM_012463.4	MANE Select	c.-170C>A		5_prime_UTR	Exon 1 of 20	NP_036595.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A2	ENST00000330342.8	TSL:1 MANE Select	c.-170C>A		5_prime_UTR	Exon 1 of 20	ENSP00000332247.2	Q9Y487
	ATP6V0A2	ENST00000613625.5	TSL:1	c.-170C>A		5_prime_UTR	Exon 1 of 9	ENSP00000482236.1	Q8TBM3
	ATP6V0A2	ENST00000858646.1		c.-170C>A		5_prime_UTR	Exon 1 of 19	ENSP00000528705.1

Frequencies

GnomAD3 genomes AF: 0.000507 AC: 77 AN: 152002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000986

Gnomad OTH AF: 0.000958

GnomAD4 exome AF: 0.000813 AC: 179 AN: 220136 Hom.: 1 Cov.: 3 AF XY: 0.000901 AC XY: 102 AN XY: 113232

African (AFR) AF: 0.000184 AC: 1 AN: 5426

American (AMR) AF: 0.000525 AC: 3 AN: 5718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7136

East Asian (EAS) AF: 0.00 AC: 0 AN: 17586

South Asian (SAS) AF: 0.000385 AC: 2 AN: 5190

European-Finnish (FIN) AF: 0.0000513 AC: 1 AN: 19486

Middle Eastern (MID) AF: 0.00179 AC: 2 AN: 1118

European-Non Finnish (NFE) AF: 0.00109 AC: 158 AN: 144664

Other (OTH) AF: 0.000869 AC: 12 AN: 13812

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74366

African (AFR) AF: 0.0000241 AC: 1 AN: 41536

American (AMR) AF: 0.000392 AC: 6 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000986 AC: 67 AN: 67948

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000477 Hom.: 0

Bravo AF: 0.000450

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cutis laxa with osteodystrophy (1)
-	1	-	Cutis Laxa, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	11
DANN	Benign	0.83
PhyloP100		0.14
PromoterAI		-0.0040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs540324717; hg19: chr12-124196943;