4-55396197-C-T

Variant names:

• chr4-55396197-C-T
• rs770675509
• NM_018475.5:c.8C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.297

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=0.24844185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM165	NM_018475.5	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 6	ENST00000381334.10	NP_060945.2
TMEM165	XM_011534394.4	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 6		XP_011532696.1
TMEM165	XM_017008412.2	c.-438C>T		5_prime_UTR_variant	Exon 1 of 8		XP_016863901.1
TMEM165	NR_073070.2	n.241C>T		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM165	ENST00000381334.10	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 6	1	NM_018475.5	ENSP00000370736.5
TMEM165	ENST00000506198.5	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 3	2		ENSP00000425449.1
TMEM165	ENST00000508404.5	n.8C>T		non_coding_transcript_exon_variant	Exon 1 of 7	2		ENSP00000422639.1
TMEM165	ENST00000514070.1	n.-54C>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000658 AC: 4 AN: 60814 Hom.: 0 AF XY: 0.0000558 AC XY: 2 AN XY: 35814

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: 4 AN: 1270296 Hom.: 0 Cov.: 29 AF XY: 0.00000321 AC XY: 2 AN XY: 623834

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.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000610 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

TMEM165-congenital disorder of glycosylation Uncertain:1

Jul 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: "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. This variant has not been reported in the literature in individuals affected with TMEM165-related conditions. 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 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.025	.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.55	T;T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.69	.;N
PrimateAI	Pathogenic	0.82	D
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	T
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

Other links and lift over

dbSNP: rs770675509; hg19: chr4-56262364;