4-55396224-C-G

Variant names:

• chr4-55396224-C-G
• rs1187840985
• NM_018475.5:c.35C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_018475.5(TMEM165):​c.35C>G​(p.Ser12Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000306 in 1,307,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: 0.0000031 (0 hom.)
• Consequence: TMEM165 NM_018475.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.28
• 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 2 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=0.31661606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM165	NM_018475.5	c.35C>G	p.Ser12Trp	missense_variant	Exon 1 of 6	ENST00000381334.10	NP_060945.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM165	ENST00000381334.10	c.35C>G	p.Ser12Trp	missense_variant	Exon 1 of 6	1	NM_018475.5	ENSP00000370736.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000306 AC: 4 AN: 1307278 Hom.: 0 Cov.: 34 AF XY: 0.00000310 AC XY: 2 AN XY: 644144

African (AFR) AF: 0.00 AC: 0 AN: 26804

American (AMR) AF: 0.00 AC: 0 AN: 25330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23030

East Asian (EAS) AF: 0.00 AC: 0 AN: 28004

South Asian (SAS) AF: 0.00 AC: 0 AN: 69086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5246

European-Non Finnish (NFE) AF: 0.00000384 AC: 4 AN: 1041770

Other (OTH) AF: 0.00 AC: 0 AN: 54164

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

TMEM165-congenital disorder of glycosylation Uncertain:1

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 12 of the TMEM165 protein (p.Ser12Trp). This variant is not present in population databases (gnomAD no frequency). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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	0.21
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Benign	0.69
DEOGEN2	Benign	0.022	.;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.73	T;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.1	.;L
PhyloP100		3.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.95	.;P
Vest4		0.34
MutPred		0.32		Loss of disorder (P = 0.0034);Loss of disorder (P = 0.0034);
MVP		0.36
MPC		0.86
ClinPred		0.83	D
GERP RS		3.6
PromoterAI		0.17	Neutral
Varity_R		0.12
gMVP		0.44
Mutation Taster		=86/14	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: rs1187840985; hg19: chr4-56262391;