4-55396241-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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 (★★). Synonymous variant affecting the same amino acid position (i.e. L18L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: TMEM165 NM_018475.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.409

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]

ACMG classification

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	UniProt
TMEM165	NM_018475.5	c.52C>A	p.Leu18Met	missense_variant	1/6	ENST00000381334.10
TMEM165	XM_011534394.4	c.52C>A	p.Leu18Met	missense_variant	1/6
TMEM165	XM_017008412.2	c.-394C>A		5_prime_UTR_variant	1/8
TMEM165	NR_073070.2	n.285C>A		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM165	ENST00000381334.10	c.52C>A	p.Leu18Met	missense_variant	1/6	1	NM_018475.5	P1
TMEM165	ENST00000506198.5	c.52C>A	p.Leu18Met	missense_variant	1/3	2
TMEM165	ENST00000508404.5	c.52C>A	p.Leu18Met	missense_variant, NMD_transcript_variant	1/7	2
TMEM165	ENST00000514070.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152074 Hom.: 0 Cov.: 32

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: 22 AN: 102576 Hom.: 0 AF XY: 0.000239 AC XY: 14 AN XY: 58688

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.: 0 Cov.: 34 AF XY: 0.000272 AC XY: 181 AN XY: 664308

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: 38 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74288

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.: 0

Bravo AF: 0.000234

ExAC AF: 0.000184 AC: 20

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

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	Invitae	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	14
Dann	Benign	0.58
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.57	T;T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.87	D
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	T
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

Other links and lift over

dbSNP: rs756276628; hg19: chr4-56262408;