dbSNP rs200901862: TMEM147:p.Gly7Arg (chr19-35545758-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS1_ModeratePM1PM2

The NM_032635.4(TMEM147):c.19G>A(p.Gly7Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,634 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TMEM147
NM_032635.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.56

Variant links:

Genes affected

TMEM147 (HGNC:30414): (transmembrane protein 147) Enables ribosome binding activity. Located in endoplasmic reticulum membrane. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

TMEM147 links:

TMEM147-AS1 (HGNC:51273): (TMEM147 antisense RNA 1)

TMEM147-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PS1

Transcript NM_032635.4 (TMEM147) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a chain BOS complex subunit TMEM147 (size 223) in uniprot entity TM147_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_032635.4

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM147	NM_032635.4 link	c.19G>A	p.Gly7Arg	missense_variant	Exon 1 of 7	ENST00000222284.10	NP_116024.1	Q9BVK8-1
TMEM147	NM_001242598.2 link	c.19G>A	p.Gly7Arg	missense_variant	Exon 1 of 5		NP_001229527.1
TMEM147	NM_001242597.2 link	c.-200G>A		5_prime_UTR_variant	Exon 1 of 6		NP_001229526.1	Q9BVK8-2
TMEM147-AS1	NR_038396.1 link	n.93+179C>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM147	ENST00000222284.10 link	c.19G>A	p.Gly7Arg	missense_variant	Exon 1 of 7	1	NM_032635.4	ENSP00000222284.4		Q9BVK8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

247848

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134404

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460634

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726696

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

T;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.67

D;D

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.9

D;D

REVEL

Uncertain

0.34

Sift

Benign

0.034

D;T

Sift4G

Uncertain

0.049

D;T

Polyphen

1.0

D;.

Vest4

0.55

MutPred

0.62

Gain of methylation at G7 (P = 0.0054);Gain of methylation at G7 (P = 0.0054);

MVP

0.19

MPC

1.2

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over