rs782067312

Variant names:

• chr11-112064196-G-A
• rs782067312
• NM_001931.5:c.*1661G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-112064196-G-A
• chr11-112064196-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001082619.2(PIH1D2):​c.839C>T​(p.Ala280Val) 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 1,565,734 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000092 (1 hom.)
• Consequence: PIH1D2 NM_001082619.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27
• Publications: 0 publications found

Genes affected

DLAT (HGNC:2896): (dihydrolipoamide S-acetyltransferase) This gene encodes component E2 of the multi-enzyme pyruvate dehydrogenase complex (PDC). PDC resides in the inner mitochondrial membrane and catalyzes the conversion of pyruvate to acetyl coenzyme A. The protein product of this gene, dihydrolipoamide acetyltransferase, accepts acetyl groups formed by the oxidative decarboxylation of pyruvate and transfers them to coenzyme A. Dihydrolipoamide acetyltransferase is the antigen for antimitochondrial antibodies. These autoantibodies are present in nearly 95% of patients with the autoimmune liver disease primary biliary cirrhosis (PBC). In PBC, activated T lymphocytes attack and destroy epithelial cells in the bile duct where this protein is abnormally distributed and overexpressed. PBC enventually leads to cirrhosis and liver failure. Mutations in this gene are also a cause of pyruvate dehydrogenase E2 deficiency which causes primary lactic acidosis in infancy and early childhood.[provided by RefSeq, Oct 2009]

PIH1D2 (HGNC:25210): (PIH1 domain containing 2) Enables small GTPase binding activity. Predicted to be involved in box C/D snoRNP assembly and rRNA processing. Predicted to be part of R2TP complex and ribonucleoprotein complex. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08384475).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001082619.2. 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
	DLAT	NM_001931.5	MANE Select	c.*1661G>A		3_prime_UTR	Exon 14 of 14	NP_001922.2
	PIH1D2	NM_001082619.2		c.839C>T	p.Ala280Val	missense	Exon 6 of 6	NP_001076088.1	Q8WWB5-2
	PIH1D2	NM_001439212.1		c.839C>T	p.Ala280Val	missense	Exon 6 of 6	NP_001426141.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLAT	ENST00000280346.11	TSL:1 MANE Select	c.*1661G>A		3_prime_UTR	Exon 14 of 14	ENSP00000280346.7	P10515
	PIH1D2	ENST00000431456.6	TSL:5	c.839C>T	p.Ala280Val	missense	Exon 6 of 6	ENSP00000388209.1	Q8WWB5-2
	PIH1D2	ENST00000528775.6	TSL:5	c.839C>T	p.Ala280Val	missense	Exon 6 of 6	ENSP00000434275.1	Q8WWB5-2

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151390 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000971

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000158 AC: 3 AN: 189392 AF XY: 0.00000986

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000763

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000919 AC: 13 AN: 1414344 Hom.: 1 Cov.: 30 AF XY: 0.00000857 AC XY: 6 AN XY: 699940

African (AFR) AF: 0.00 AC: 0 AN: 32628

American (AMR) AF: 0.000108 AC: 4 AN: 37088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25256

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38198

South Asian (SAS) AF: 0.0000376 AC: 3 AN: 79886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1087818

Other (OTH) AF: 0.0000342 AC: 2 AN: 58398

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151390 Hom.: 0 Cov.: 32 AF XY: 0.0000406 AC XY: 3 AN XY: 73900

African (AFR) AF: 0.0000971 AC: 4 AN: 41214

American (AMR) AF: 0.00 AC: 0 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67864

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000836 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.0
DANN	Benign	0.42
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.3
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.017
Sift	Benign	0.81	T
Sift4G	Benign	0.13	T
Vest4		0.11
MutPred		0.44		Gain of methylation at K281 (P = 0.0385)
MVP		0.33
ClinPred		0.012	T
GERP RS		2.1
Mutation Taster		=97/3	polymorphism

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: rs782067312; hg19: chr11-111934920;