Genetic Variant MPZL3:p.Val172Met (chr11-118235527-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198275.3(MPZL3):c.514G>A(p.Val172Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,613,912 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0058 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00081 ( 6 hom. )

Consequence

MPZL3
NM_198275.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.590

Publications

4 publications found

Variant links:

Genes affected

MPZL3 (HGNC:27279): (myelin protein zero like 3) Predicted to be involved in cell adhesion. Predicted to act upstream of or within extracellular matrix organization and hair cycle. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

MPZL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008910626).

BP6

Variant 11-118235527-C-T is Benign according to our data. Variant chr11-118235527-C-T is described in ClinVar as Benign. ClinVar VariationId is 776663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00584 (888/152164) while in subpopulation AFR AF = 0.0175 (725/41492). AF 95% confidence interval is 0.0164. There are 5 homozygotes in GnomAd4. There are 421 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198275.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MPZL3	NM_198275.3	MANE Select	c.514G>A	p.Val172Met	missense	Exon 4 of 6	NP_938016.1	Q6UWV2-1
MPZL3	NM_001286152.2		c.478G>A	p.Val160Met	missense	Exon 4 of 6	NP_001273081.1	Q6UWV2-2
MPZL3	NR_104405.2		n.374G>A		non_coding_transcript_exon	Exon 3 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MPZL3	ENST00000278949.9	TSL:1 MANE Select	c.514G>A	p.Val172Met	missense	Exon 4 of 6	ENSP00000278949.4	Q6UWV2-1
MPZL3	ENST00000527472.1	TSL:1	c.478G>A	p.Val160Met	missense	Exon 4 of 6	ENSP00000432106.1	Q6UWV2-2
MPZL3	ENST00000525386.5	TSL:1	c.74-2004G>A		intron	N/A	ENSP00000434636.1	E9PPB1

Frequencies

GnomAD3 genomes

AF:

0.00586

AC:

891

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00833

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00183

AC:

458

AN:

250950

AF XY:

0.00135

show subpopulations

Gnomad AFR exome

AF:

0.0190

Gnomad AMR exome

AF:

0.00275

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000335

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.000808

AC:

1181

AN:

1461748

Hom.:

Cov.:

AF XY:

0.000729

AC XY:

530

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.0171

AC:

571

AN:

33464

American (AMR)

AF:

0.00347

AC:

155

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000290

AC:

322

AN:

1111928

Other (OTH)

AF:

0.00184

AC:

111

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

137

206

274

343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00584

AC:

888

AN:

152164

Hom.:

Cov.:

AF XY:

0.00566

AC XY:

421

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0175

AC:

725

AN:

41492

American (AMR)

AF:

0.00831

AC:

127

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68016

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

135

180

225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00129

Hom.:

Bravo

AF:

0.00777

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0141

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.00191

AC:

232

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000474

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0089

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

1.9

PhyloP100

0.59

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.36

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.011

Polyphen

0.90

Vest4

0.39

MVP

0.46

MPC

0.090

ClinPred

0.019

GERP RS

4.0

Varity_R

0.054

gMVP

0.37

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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