dbSNP rs1036333511: TMEM165:p.Arg42Gly (chr4-55396313-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_018475.5(TMEM165):c.124C>G(p.Arg42Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,374,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. R42W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

TMEM165
NM_018475.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.176

Variant links:

Genes affected

TMEM165 (HGNC:30760): (transmembrane protein 165) This gene encodes a predicted transmembrane protein with a perinuclear Golgi-like distribution in fibroblasts. Mutations in this gene are associated with the autosomal recessive disorder congenital disorder of glycosylation, type IIk. Knockdown of this gene's expression causes decreased sialylation in HEK cells and suggests this gene plays a role in terminal Golgi glycosylation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

TMEM165 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a chain Transmembrane protein 165 (size 290) in uniprot entity TM165_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_018475.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2666567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM165	NM_018475.5 link	c.124C>G	p.Arg42Gly	missense_variant	Exon 1 of 6	ENST00000381334.10	NP_060945.2	Q9HC07-1
TMEM165	XM_011534394.4 link	c.124C>G	p.Arg42Gly	missense_variant	Exon 1 of 6		XP_011532696.1
TMEM165	XM_017008412.2 link	c.-322C>G		5_prime_UTR_variant	Exon 1 of 8		XP_016863901.1	Q9HC07-2
TMEM165	NR_073070.2 link	n.357C>G		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM165	ENST00000381334.10 link	c.124C>G	p.Arg42Gly	missense_variant	Exon 1 of 6	1	NM_018475.5	ENSP00000370736.5	Q9HC07-1
TMEM165	ENST00000506198.5 link	c.124C>G	p.Arg42Gly	missense_variant	Exon 1 of 3	2		ENSP00000425449.1	D6RD79
TMEM165	ENST00000508404.5 link	n.124C>G		non_coding_transcript_exon_variant	Exon 1 of 7	2		ENSP00000422639.1	D6RBL0
TMEM165	ENST00000514070.1 link	n.63C>G		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000835

AC:

AN:

119766

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

67026

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000443

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

7.27e-7

AC:

AN:

1374706

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

679402

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000287

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

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

Benign

0.087

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.026

.;T

Eigen

Benign

0.11

Eigen_PC

Benign

0.064

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.79

T;T

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.27

T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.6

.;L

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

0.23

N;N

REVEL

Benign

0.28

Sift

Uncertain

0.021

D;D

Sift4G

Pathogenic

0.0

D;T

Polyphen

0.99

.;D

Vest4

0.42

MutPred

0.15

Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);

MVP

0.49

MPC

1.6

ClinPred

0.53

GERP RS

4.2

Varity_R

0.28

gMVP

0.42

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

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