rs1044322

Variant names:

• chr10-87863566-G-A
• rs1044322
• ENST00000692337.1:c.8G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-87863566-G-A
• chr10-87863566-G-C
• chr10-87863566-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000692337.1(MLDHR):​c.8G>A​(p.Arg3Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 386,948 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 4/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., cov: 32)
  • Exomes 𝑓: 0.015 (41 hom.)
• Consequence: MLDHR ENST00000692337.1 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:6
• Conservation: PhyloP100: 1.84
• Publications: 10 publications found

Genes affected

MLDHR (HGNC:55481):

PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

KLLN (HGNC:37212): (killin, p53 regulated DNA replication inhibitor) The protein encoded by this intronless gene is found in the nucleus, where it can inhibit DNA synthesis and promote S phase arrest coupled to apoptosis. The expression of this DNA binding protein is upregulated by transcription factor p53. [provided by RefSeq, Dec 2012]

KLLN Gene-Disease associations (from GenCC):

• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden syndrome 4

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 10-87863566-G-A is Benign according to our data. Variant chr10-87863566-G-A is described in ClinVar as Benign. ClinVar VariationId is 138837.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0123 (1871/152120) while in subpopulation NFE AF = 0.0167 (1133/67952). AF 95% confidence interval is 0.0159. There are 22 homozygotes in GnomAd4. There are 879 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.-904G>A		upstream_gene_variant		ENST00000371953.8	NP_000305.3
KLLN	NM_001126049.2	c.-1079C>T		upstream_gene_variant		ENST00000445946.5	NP_001119521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLDHR	ENST00000692337.1	c.8G>A	p.Arg3Gln	missense_variant	Exon 1 of 1			ENSP00000509326.1
PTEN	ENST00000371953.8	c.-904G>A		upstream_gene_variant		1	NM_000314.8	ENSP00000361021.3
KLLN	ENST00000445946.5	c.-1079C>T		upstream_gene_variant		6	NM_001126049.2	ENSP00000392204.2

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1872 AN: 152012 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00601

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00194

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.0155 AC: 3630 AN: 234828 Hom.: 41 Cov.: 0 AF XY: 0.0157 AC XY: 1880 AN XY: 119370

African (AFR) AF: 0.00603 AC: 40 AN: 6630

American (AMR) AF: 0.0146 AC: 102 AN: 6982

Ashkenazi Jewish (ASJ) AF: 0.0203 AC: 175 AN: 8632

East Asian (EAS) AF: 0.00126 AC: 28 AN: 22278

South Asian (SAS) AF: 0.00431 AC: 12 AN: 2782

European-Finnish (FIN) AF: 0.0119 AC: 245 AN: 20598

Middle Eastern (MID) AF: 0.0351 AC: 43 AN: 1224

European-Non Finnish (NFE) AF: 0.0184 AC: 2763 AN: 150280

Other (OTH) AF: 0.0144 AC: 222 AN: 15422

GnomAD4 genome AF: 0.0123 AC: 1871 AN: 152120 Hom.: 22 Cov.: 32 AF XY: 0.0118 AC XY: 879 AN XY: 74362

African (AFR) AF: 0.00599 AC: 249 AN: 41556

American (AMR) AF: 0.0132 AC: 201 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3470

East Asian (EAS) AF: 0.00194 AC: 10 AN: 5150

South Asian (SAS) AF: 0.00600 AC: 29 AN: 4830

European-Finnish (FIN) AF: 0.0117 AC: 124 AN: 10572

Middle Eastern (MID) AF: 0.0514 AC: 15 AN: 292

European-Non Finnish (NFE) AF: 0.0167 AC: 1133 AN: 67952

Other (OTH) AF: 0.0128 AC: 27 AN: 2108

Alfa AF: 0.0131 Hom.: 13

Bravo AF: 0.0120

Asia WGS AF: 0.00409 AC: 14 AN: 3440

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 30, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 08, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 29, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-903G>A variant is located in the 5' untranslated region (5’ UTR) of the PTEN gene. This variant results from a G to A substitution 903 bases upstream from the first translated codon. This variant is located in the promoter region of the PTEN gene, but its potential impact on PTEN regulation has not yet been investigated (Zhou XP et al. Am. J. Hum. Genet. 2003 Aug;73:404-11). This nucleotide position is well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

PTEN hamartoma tumor syndrome Benign:1

Sep 14, 2016

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

PTEN c.-903G>A (NC_000010.10:g.89623323G>A) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). BA1: Allele frequency of 0.011 (1.1%, 343/30,808 alleles) in the gnomAD cohort. (PMID 27535533) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Benign	0.96
PhyloP100		1.8
PromoterAI		0.21	Neutral
Mutation Taster		=298/2	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: rs1044322; hg19: chr10-89623323;