dbSNP rs779573037: TMEM151B:p.Val193Ile (chr6-44275403-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001137560.2(TMEM151B):c.577G>A(p.Val193Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000397 in 1,513,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V193F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

TMEM151B
NM_001137560.2 missense, splice_region

Scores

Splicing: ADA: 0.9978

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.90

Publications

0 publications found

Variant links:

Genes affected

TMEM151B (HGNC:21315): (transmembrane protein 151B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM151B links:

ENSG00000272442 (HGNC:):

ENSG00000272442 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001137560.2. 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
	TMEM151B	NM_001137560.2	MANE Select	c.577G>A	p.Val193Ile	missense splice_region	Exon 3 of 3	NP_001131032.1	Q8IW70-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM151B	ENST00000451188.7	TSL:5 MANE Select	c.577G>A	p.Val193Ile	missense splice_region	Exon 3 of 3	ENSP00000393161.2	Q8IW70-1
ENSG00000272442	ENST00000505802.1	TSL:2	n.312+1897G>A		intron	N/A	ENSP00000424257.1	H0Y9J4
TMEM151B	ENST00000438774.2	TSL:3	c.576+1897G>A		intron	N/A	ENSP00000409337.2	Q8IW70-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

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:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000801

AC:

AN:

124884

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000220

AC:

AN:

1360834

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

666164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30590

American (AMR)

AF:

0.00

AC:

AN:

32474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23540

East Asian (EAS)

AF:

0.00

AC:

AN:

35046

South Asian (SAS)

AF:

0.0000397

AC:

AN:

75482

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5036

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1057744

Other (OTH)

AF:

0.00

AC:

AN:

56236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

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:

0.0000197

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000414

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000422

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.087

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.0099

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.4

PhyloP100

4.9

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.86

REVEL

Uncertain

0.38

Sift

Benign

0.040

Sift4G

Benign

0.075

Polyphen

0.69

Vest4

0.22

MutPred

0.54

Gain of catalytic residue at V193 (P = 0.0482)

MVP

0.055

ClinPred

0.64

GERP RS

4.7

Varity_R

0.20

gMVP

0.64

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.76

SpliceAI score (max)

0.12

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