Genetic Variant TMEM121B:p.Arg470Pro (chr22-17119719-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_031890.4(TMEM121B):c.1409G>C(p.Arg470Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000259 in 1,542,336 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R470H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

TMEM121B
NM_031890.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.27

Publications

0 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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.1409G>C	p.Arg470Pro	missense	Exon 1 of 1	NP_114096.1	Q9BXQ6-1
	TMEM121B	NM_001163079.2		c.344G>C	p.Arg115Pro	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.1409G>C	p.Arg470Pro	missense	Exon 1 of 1	ENSP00000329318.3	Q9BXQ6-1
TMEM121B	ENST00000399875.1	TSL:2	c.344G>C	p.Arg115Pro	missense	Exon 2 of 2	ENSP00000382764.1	Q9BXQ6-2
LINC01664	ENST00000846293.1		n.201C>G		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000216

AC:

AN:

1390122

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

686710

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31960

American (AMR)

AF:

0.00

AC:

AN:

36012

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25184

East Asian (EAS)

AF:

0.00

AC:

AN:

36424

South Asian (SAS)

AF:

0.00

AC:

AN:

80028

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33966

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5560

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1082856

Other (OTH)

AF:

0.0000172

AC:

AN:

58132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.59

M_CAP

Benign

0.069

MetaRNN

Uncertain

0.62

MetaSVM

Benign

-0.53

PhyloP100

4.3

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.35

Sift

Uncertain

0.019

Sift4G

Uncertain

0.025

Polyphen

1.0

Vest4

0.71

MutPred

0.44

Gain of glycosylation at R470 (P = 0.0859)

MVP

0.40

ClinPred

1.0

GERP RS

4.3

Varity_R

0.91

gMVP

0.86

Mutation Taster

=35/65

disease causing

(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