chr4-55396197-C-T

Position:

chr4-55396197-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018475.5(TMEM165):c.8C>T(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000315 in 1,270,296 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: not found (cov: 32)

Exomes 𝑓: 0.0000031 ( 0 hom. )

Consequence

TMEM165
NM_018475.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.297

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24844185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMEM165	NM_018475.5 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	1/6	ENST00000381334.10	NP_060945.2
TMEM165	XM_011534394.4 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	1/6		XP_011532696.1
TMEM165	XM_017008412.2 linkuse as main transcript	c.-438C>T		5_prime_UTR_variant	1/8		XP_016863901.1
TMEM165	NR_073070.2 linkuse as main transcript	n.241C>T		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM165	ENST00000381334.10 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	1/6	1	NM_018475.5	ENSP00000370736	P1	Q9HC07-1
TMEM165	ENST00000506198.5 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	1/3	2		ENSP00000425449
TMEM165	ENST00000508404.5 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant, NMD_transcript_variant	1/7	2		ENSP00000422639

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000658

AC:

AN:

60814

Hom.:

AF XY:

0.0000558

AC XY:

AN XY:

35814

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000421

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:

0.00000315

AC:

AN:

1270296

Hom.:

Cov.:

AF XY:

0.00000321

AC XY:

AN XY:

623834

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000203

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.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000610

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

TMEM165-congenital disorder of glycosylation

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 25, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3 of the TMEM165 protein (p.Ala3Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TMEM165-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.025

.;T

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.55

T;T

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.43

MutationAssessor

Benign

0.69

.;N

MutationTaster

Benign

0.73

D;D;N

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.61

N;N

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.027

D;T

Polyphen

0.98

.;D

Vest4

0.22

MutPred

0.25

Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);

MVP

0.24

MPC

0.62

ClinPred

0.16

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.086

gMVP

0.51

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over