4-55396241-C-A

Position:

chr4-55396241-C-A

Variant summary

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

The NM_018475.5(TMEM165):c.52C>A(p.Leu18Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,496,596 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. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

TMEM165
NM_018475.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.409

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=0.09977156).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM165	NM_018475.5 link	c.52C>A	p.Leu18Met	missense_variant	1/6	ENST00000381334.10	NP_060945.2	Q9HC07-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM165	ENST00000381334.10 link	c.52C>A	p.Leu18Met	missense_variant	1/6	1	NM_018475.5	ENSP00000370736.5	Q9HC07-1
TMEM165	ENST00000506198.5 link	c.52C>A	p.Leu18Met	missense_variant	1/3	2		ENSP00000425449.1	D6RD79
TMEM165	ENST00000508404.5 link	n.52C>A		non_coding_transcript_exon_variant	1/7	2		ENSP00000422639.1	D6RBL0
TMEM165	ENST00000514070.1 link	n.-10C>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000214

AC:

AN:

102576

Hom.:

AF XY:

0.000239

AC XY:

AN XY:

58688

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000531

Gnomad ASJ exome

AF:

0.000577

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000161

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000339

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000242

AC:

326

AN:

1344522

Hom.:

Cov.:

AF XY:

0.000272

AC XY:

181

AN XY:

664308

show subpopulations

Gnomad4 AFR exome

AF:

0.0000364

Gnomad4 AMR exome

AF:

0.0000666

Gnomad4 ASJ exome

AF:

0.000883

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000429

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000236

Gnomad4 OTH exome

AF:

0.000286

GnomAD4 genome

AF:

0.000250

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000231

Hom.:

Bravo

AF:

0.000234

ExAC

AF:

0.000184

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

TMEM165-congenital disorder of glycosylation

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 21, 2022	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 18 of the TMEM165 protein (p.Leu18Met). This variant is present in population databases (rs756276628, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with TMEM165-related conditions. ClinVar contains an entry for this variant (Variation ID: 976570). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2023

The c.52C>A (p.L18M) alteration is located in exon 1 (coding exon 1) of the TMEM165 gene. This alteration results from a C to A substitution at nucleotide position 52, causing the leucine (L) at amino acid position 18 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 09, 2024

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.58

DEOGEN2

Benign

0.036

.;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.57

T;T

M_CAP

Pathogenic

0.85

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.8

.;L

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.0

N;N

REVEL

Benign

0.10

Sift

Uncertain

0.0040

D;T

Sift4G

Pathogenic

0.0

D;T

Polyphen

0.23

.;B

Vest4

0.29

MutPred

0.36

Gain of catalytic residue at L18 (P = 0.0319);Gain of catalytic residue at L18 (P = 0.0319);

MVP

0.45

MPC

0.77

ClinPred

0.053

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.069

gMVP

0.31

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