10-124461881-C-T

Variant names:

• chr10-124461881-C-T
• rs767909716
• NM_022126.4:c.19C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022126.4(LHPP):​c.19C>T​(p.Arg7Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000398 in 1,257,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: LHPP NM_022126.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.956
• Publications: 0 publications found

Genes affected

LHPP (HGNC:30042): (phospholysine phosphohistidine inorganic pyrophosphate phosphatase) Enables inorganic diphosphatase activity and protein homodimerization activity. Involved in phosphate-containing compound metabolic process. Located in cytosol and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34757912).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022126.4. 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
	LHPP	NM_022126.4	MANE Select	c.19C>T	p.Arg7Trp	missense	Exon 1 of 7	NP_071409.3
	LHPP	NM_001318332.2		c.19C>T	p.Arg7Trp	missense	Exon 1 of 6	NP_001305261.1	Q5T1Z0
	LHPP	NM_001167880.2		c.19C>T	p.Arg7Trp	missense	Exon 1 of 6	NP_001161352.1	Q9H008-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHPP	ENST00000368842.10	TSL:1 MANE Select	c.19C>T	p.Arg7Trp	missense	Exon 1 of 7	ENSP00000357835.5	Q9H008-1
	LHPP	ENST00000368839.1	TSL:1	c.19C>T	p.Arg7Trp	missense	Exon 1 of 6	ENSP00000357832.1	Q9H008-2
	LHPP	ENST00000890879.1		c.19C>T	p.Arg7Trp	missense	Exon 1 of 7	ENSP00000560938.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151902 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000446 AC: 2 AN: 44868 AF XY: 0.0000406

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000273

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000403

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000362 AC: 4 AN: 1105558 Hom.: 0 Cov.: 33 AF XY: 0.00000380 AC XY: 2 AN XY: 525640

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23734

American (AMR) AF: 0.00 AC: 0 AN: 11088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13992

East Asian (EAS) AF: 0.0000356 AC: 1 AN: 28096

South Asian (SAS) AF: 0.00 AC: 0 AN: 21638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2994

European-Non Finnish (NFE) AF: 0.00000323 AC: 3 AN: 929990

Other (OTH) AF: 0.00 AC: 0 AN: 43828

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0867841), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151902 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74198

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67938

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

Alfa AF: 0.0000843 Hom.: 0

ExAC AF: 0.0000195 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3468

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	Uncertain	0.35
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0063	T
Eigen	Benign	0.056
Eigen_PC	Benign	-0.0049
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.96
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.12
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.023	D
Polyphen		0.99	D
Vest4		0.48
MutPred		0.44		Loss of disorder (P = 0.0233)
MVP		0.25
MPC		0.21
ClinPred		0.29	T
GERP RS		3.5
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.48
gMVP		0.55
Mutation Taster		=69/31	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: rs767909716; hg19: chr10-126150450;