4-55396230-C-T

Variant names:

• chr4-55396230-C-T
• rs2109509637
• NM_018475.5:c.41C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_018475.5(TMEM165):​c.41C>T​(p.Pro14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000378 in 1,321,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P14S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: TMEM165 NM_018475.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0540
• Publications: 0 publications found

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]

SRD5A3-AS1 (HGNC:44138): (SRD5A3 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.3658 (below the threshold of 3.09). Trascript score misZ: 0.68834 (below the threshold of 3.09). GenCC associations: The gene is linked to TMEM165-congenital disorder of glycosylation.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12558177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM165	NM_018475.5	c.41C>T	p.Pro14Leu	missense_variant	Exon 1 of 6	ENST00000381334.10	NP_060945.2
TMEM165	XM_011534394.4	c.41C>T	p.Pro14Leu	missense_variant	Exon 1 of 6		XP_011532696.1
TMEM165	NR_073070.2	n.274C>T		non_coding_transcript_exon_variant	Exon 1 of 7
TMEM165	XM_017008412.2	c.-405C>T		5_prime_UTR_variant	Exon 1 of 8		XP_016863901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM165	ENST00000381334.10	c.41C>T	p.Pro14Leu	missense_variant	Exon 1 of 6	1	NM_018475.5	ENSP00000370736.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000378 AC: 5 AN: 1321046 Hom.: 0 Cov.: 33 AF XY: 0.00000614 AC XY: 4 AN XY: 651752

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26990

American (AMR) AF: 0.00 AC: 0 AN: 26444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23362

East Asian (EAS) AF: 0.00 AC: 0 AN: 28370

South Asian (SAS) AF: 0.00 AC: 0 AN: 71738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34614

Middle Eastern (MID) AF: 0.000371 AC: 2 AN: 5388

European-Non Finnish (NFE) AF: 0.00000191 AC: 2 AN: 1049282

Other (OTH) AF: 0.0000182 AC: 1 AN: 54858

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.003849), which strongly suggests a high chance of mosaicism in these individuals.

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

Sep 18, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with leucine at codon 14 of the TMEM165 protein (p.Pro14Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC 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 leucine 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	Benign	0.30
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.86
DEOGEN2	Benign	0.021	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.57	T;T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.69	.;N
PhyloP100		0.054
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0050	D;T
Polyphen		0.0	.;B
Vest4		0.10
MutPred		0.34		Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);
MVP		0.12
MPC		0.64
ClinPred		0.10	T
GERP RS		0.16
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.030
gMVP		0.34
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs2109509637; hg19: chr4-56262397;