Genetic Variant TMEM121B:p.Pro548His (chr22-17119485-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_031890.4(TMEM121B):c.1643C>A(p.Pro548His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000574 in 1,601,738 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 Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

TMEM121B
NM_031890.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.76

Publications

2 publications found

Variant links:

Genes affected

TMEM121B (HGNC:1844): (transmembrane protein 121B)

TMEM121B links:

LINC01664 (HGNC:52452): (long intergenic non-protein coding RNA 1664)

LINC01664 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19616002).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031890.4. 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
	TMEM121B	NM_031890.4	MANE Select	c.1643C>A	p.Pro548His	missense	Exon 1 of 1	NP_114096.1	Q9BXQ6-1
	TMEM121B	NM_001163079.2		c.578C>A	p.Pro193His	missense	Exon 2 of 2	NP_001156551.1	Q9BXQ6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM121B	ENST00000331437.4	TSL:6 MANE Select	c.1643C>A	p.Pro548His	missense	Exon 1 of 1	ENSP00000329318.3	Q9BXQ6-1
TMEM121B	ENST00000399875.1	TSL:2	c.578C>A	p.Pro193His	missense	Exon 2 of 2	ENSP00000382764.1	Q9BXQ6-2
LINC01664	ENST00000846293.1		n.-34G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD2 exomes

AF:

0.0000178

AC:

AN:

225226

AF XY:

0.00000818

show subpopulations

Gnomad AFR exome

AF:

0.0000734

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:

0.0000201

Gnomad OTH exome

AF:

0.000179

GnomAD4 exome

AF:

0.0000614

AC:

AN:

1449536

Hom.:

Cov.:

AF XY:

0.0000667

AC XY:

AN XY:

720022

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33146

American (AMR)

AF:

0.00

AC:

AN:

43328

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25862

East Asian (EAS)

AF:

0.00

AC:

AN:

38988

South Asian (SAS)

AF:

0.00

AC:

AN:

84112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52178

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

0.0000786

AC:

AN:

1106374

Other (OTH)

AF:

0.0000334

AC:

AN:

59876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000430

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.020

Eigen

Benign

0.048

Eigen_PC

Benign

-0.050

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.46

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.95

PhyloP100

1.8

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.069

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.29

MVP

0.23

ClinPred

0.45

GERP RS

2.7

Varity_R

0.17

gMVP

0.18

Mutation Taster

=94/6

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over