4-55396332-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_018475.5(TMEM165):c.143C>T(p.Ala48Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000732 in 1,365,318 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: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: TMEM165 NM_018475.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.899

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 2 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=0.19424391).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM165	NM_018475.5	c.143C>T	p.Ala48Val	missense_variant	1/6	ENST00000381334.10
TMEM165	XM_011534394.4	c.143C>T	p.Ala48Val	missense_variant	1/6
TMEM165	XM_017008412.2	c.-303C>T		5_prime_UTR_variant	1/8
TMEM165	NR_073070.2	n.376C>T		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM165	ENST00000381334.10	c.143C>T	p.Ala48Val	missense_variant	1/6	1	NM_018475.5	P1
TMEM165	ENST00000506198.5	c.143C>T	p.Ala48Val	missense_variant	1/3	2
TMEM165	ENST00000514070.1	n.82C>T		non_coding_transcript_exon_variant	1/2	2
TMEM165	ENST00000508404.5	c.143C>T	p.Ala48Val	missense_variant, NMD_transcript_variant	1/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.32e-7 AC: 1 AN: 1365318 Hom.: 0 Cov.: 34 AF XY: 0.00000148 AC XY: 1 AN XY: 674050

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.35e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

TMEM165-congenital disorder of glycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 08, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; 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. This variant has not been reported in the literature in individuals affected with TMEM165-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 48 of the TMEM165 protein (p.Ala48Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	18
Dann	Benign	0.87
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.66	T;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.43	N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0070	D;T
Sift4G	Pathogenic	0.0	D;T
Polyphen		0.0020	.;B
Vest4		0.33
MutPred		0.12		Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.17
MPC		1.4
ClinPred		0.51	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.023
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-56262499;