NM_000053.4:c.2972C>T

Variant names:

• chr13-51946372-G-A
• rs41292782
• NM_000053.4:c.2972C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 9P and 4B. PS3 PM1 PM5 PP2 BS2

The NM_000053.4(ATP7B):​c.2972C>T​(p.Thr991Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,613,596 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000052008: The most pronounced variant effect results in a mild/intermediate deficit when assessing the ability to complement ccc2, the yeast copper-transporting orthologue of ATP7B, function under low iron conditions at 30 degree C and 37 degree C (Luoma_2010)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T991A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (10 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:15
• Conservation: PhyloP100: 9.94
• Publications: 18 publications found

Genes affected

ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]

ATP7B Gene-Disease associations (from GenCC):

• Wilson disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000052008: The most pronounced variant effect results in a mild/intermediate deficit when assessing the ability to complement ccc2, the yeast copper-transporting orthologue of ATP7B, function under low iron conditions at 30 degree C and 37 degree C (Luoma_2010).; SCV000626848: Experimental studies have shown that this missense change affects ATP7B function (PMID: 20333758).
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000053.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-51946373-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1172921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 198 curated pathogenic missense variants (we use a threshold of 10). The gene has 32 curated benign missense variants. Gene score misZ: -0.88091 (below the threshold of 3.09). Trascript score misZ: 0.82063 (below the threshold of 3.09). GenCC associations: The gene is linked to Wilson disease.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000053.4. 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
	ATP7B	NM_000053.4	MANE Select	c.2972C>T	p.Thr991Met	missense	Exon 13 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.2972C>T	p.Thr991Met	missense	Exon 14 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.2972C>T	p.Thr991Met	missense	Exon 14 of 22	NP_001393441.1	P35670-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	ENST00000242839.10	TSL:1 MANE Select	c.2972C>T	p.Thr991Met	missense	Exon 13 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.2828C>T	p.Thr943Met	missense	Exon 13 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000448424.7	TSL:1	c.2720C>T	p.Thr907Met	missense	Exon 11 of 19	ENSP00000416738.3	E7ET55

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 226 AN: 152238 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00291

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00120 AC: 298 AN: 248580 AF XY: 0.00120

Gnomad AFR exome AF: 0.000454

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.000280

Gnomad NFE exome AF: 0.00236

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00340 AC: 4963 AN: 1461240 Hom.: 10 Cov.: 32 AF XY: 0.00325 AC XY: 2363 AN XY: 726878

African (AFR) AF: 0.000747 AC: 25 AN: 33468

American (AMR) AF: 0.000313 AC: 14 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86164

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5436

European-Non Finnish (NFE) AF: 0.00431 AC: 4788 AN: 1111898

Other (OTH) AF: 0.00162 AC: 98 AN: 60338

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152356 Hom.: 2 Cov.: 33 AF XY: 0.00138 AC XY: 103 AN XY: 74514

African (AFR) AF: 0.000457 AC: 19 AN: 41590

American (AMR) AF: 0.000327 AC: 5 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

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

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00291 AC: 198 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00184 Hom.: 0

Bravo AF: 0.00149

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000750 AC: 3

ESP6500EA AF: 0.00240 AC: 20

ExAC AF: 0.00118 AC: 143

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00255

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	9	-	Wilson disease (12)
1	4	-	not provided (5)
-	1	-	ATP7B-related disorder (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.98
MPC		0.38
ClinPred		0.13	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.90
Mutation Taster		=1/99	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: rs41292782; hg19: chr13-52520508;