chr10-124461978-C-T

Variant names:

• chr10-124461978-C-T
• rs1281389112
• NM_022126.4:c.116C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022126.4(LHPP):​c.116C>T​(p.Ala39Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 1,217,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: LHPP NM_022126.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.93
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

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.116C>T	p.Ala39Val	missense	Exon 1 of 7	NP_071409.3
	LHPP	NM_001318332.2		c.116C>T	p.Ala39Val	missense	Exon 1 of 6	NP_001305261.1	Q5T1Z0
	LHPP	NM_001167880.2		c.116C>T	p.Ala39Val	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.116C>T	p.Ala39Val	missense	Exon 1 of 7	ENSP00000357835.5	Q9H008-1
	LHPP	ENST00000368839.1	TSL:1	c.116C>T	p.Ala39Val	missense	Exon 1 of 6	ENSP00000357832.1	Q9H008-2
	LHPP	ENST00000890879.1		c.116C>T	p.Ala39Val	missense	Exon 1 of 7	ENSP00000560938.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151770 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: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000563 AC: 6 AN: 1065962 Hom.: 0 Cov.: 33 AF XY: 0.00000199 AC XY: 1 AN XY: 503494

African (AFR) AF: 0.00 AC: 0 AN: 22196

American (AMR) AF: 0.00 AC: 0 AN: 7768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13322

East Asian (EAS) AF: 0.00 AC: 0 AN: 25024

South Asian (SAS) AF: 0.00 AC: 0 AN: 19472

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2814

European-Non Finnish (NFE) AF: 0.00000661 AC: 6 AN: 908264

Other (OTH) AF: 0.00 AC: 0 AN: 42152

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151770 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74148

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

African (AFR) AF: 0.00 AC: 0 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10514

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

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67884

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.037	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.9
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.28
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.76		Gain of MoRF binding (P = 0.1182)
MVP		0.19
MPC		0.53
ClinPred		1.0	D
GERP RS		4.3
PromoterAI		0.057	Neutral
Varity_R		0.98
gMVP		0.70
Mutation Taster		=12/88	disease causing

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: rs1281389112; hg19: chr10-126150547;