4-55396230-C-T

Position:

• chr4-55396230-C-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.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. 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: 0.0000038 (0 hom.)
• Consequence: TMEM165 NM_018475.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0540

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=0.12558177).

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM165	ENST00000381334.10	c.41C>T	p.Pro14Leu	missense_variant	1/6	1	NM_018475.5	ENSP00000370736	P1
TMEM165	ENST00000506198.5	c.41C>T	p.Pro14Leu	missense_variant	1/3	2		ENSP00000425449
TMEM165	ENST00000508404.5	c.41C>T	p.Pro14Leu	missense_variant, NMD_transcript_variant	1/7	2		ENSP00000422639
TMEM165	ENST00000514070.1			upstream_gene_variant		2

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

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: 0.00000191

Gnomad4 OTH exome AF: 0.0000182

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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 18, 2021

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
MutationTaster	Benign	1.0	N;N;N
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.030
gMVP		0.34

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: chr4-56262397;