Genetic Variant MLDHR:p.Ser25Ser (chr10-87863633-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2BP4_ModerateBP6_Very_StrongBP7

The NM_001433720.1(MLDHR):c.75C>T(p.Ser25Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000485 in 391,412 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 Likely benign (★★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

MLDHR
NM_001433720.1 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:1

Conservation

PhyloP100: 0.782

Publications

0 publications found

Variant links:

Genes affected

MLDHR (HGNC:55481):

MLDHR links:

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]

PTEN links:

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

KLLN links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BP6

Variant 10-87863633-C-T is Benign according to our data. Variant chr10-87863633-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 189497.Status of the report is reviewed_by_expert_panel, 3 stars.

BP7

Synonymous conserved (PhyloP=0.782 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001433720.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTEN	NM_000314.8	MANE Select	c.-837C>T		5_prime_UTR	Exon 1 of 9	NP_000305.3
MLDHR	NM_001433720.1		c.75C>T	p.Ser25Ser	synonymous	Exon 1 of 1	NP_001420649.1	C0HLV8
PTEN	NM_001304717.5		c.-317C>T		5_prime_UTR	Exon 1 of 10	NP_001291646.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MLDHR	ENST00000692337.1		c.75C>T	p.Ser25Ser	synonymous	Exon 1 of 1	ENSP00000509326.1	C0HLV8
PTEN	ENST00000371953.8	TSL:1 MANE Select	c.-837C>T		5_prime_UTR	Exon 1 of 9	ENSP00000361021.3	P60484-1
PTEN	ENST00000693560.1		c.-317C>T		5_prime_UTR	Exon 1 of 10	ENSP00000509861.1	A0A8I5KSF9

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000501

AC:

AN:

239332

Hom.:

Cov.:

AF XY:

0.0000493

AC XY:

AN XY:

121594

show subpopulations

African (AFR)

AF:

0.000294

AC:

AN:

6798

American (AMR)

AF:

0.00

AC:

AN:

7178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8846

East Asian (EAS)

AF:

0.0000443

AC:

AN:

22548

South Asian (SAS)

AF:

0.00

AC:

AN:

2982

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20708

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1254

European-Non Finnish (NFE)

AF:

0.0000587

AC:

AN:

153224

Other (OTH)

AF:

0.00

AC:

AN:

15794

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.546

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41448

American (AMR)

AF:

0.0000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67978

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000267

Hom.:

Bravo

AF:

0.0000529

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

PTEN hamartoma tumor syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

0.78

PromoterAI

0.075

Neutral

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over