4-55396281-T-C

Variant names:

• chr4-55396281-T-C
• rs1720719387
• NM_018475.5:c.92T>C

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.92T>C​(p.Val31Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000292 in 1,371,832 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: TMEM165 NM_018475.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.120
• 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=0.11180201).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM165	NM_018475.5	c.92T>C	p.Val31Ala	missense_variant	Exon 1 of 6	ENST00000381334.10	NP_060945.2
TMEM165	XM_011534394.4	c.92T>C	p.Val31Ala	missense_variant	Exon 1 of 6		XP_011532696.1
TMEM165	NR_073070.2	n.325T>C		non_coding_transcript_exon_variant	Exon 1 of 7
TMEM165	XM_017008412.2	c.-354T>C		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.92T>C	p.Val31Ala	missense_variant	Exon 1 of 6	1	NM_018475.5	ENSP00000370736.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000292 AC: 4 AN: 1371832 Hom.: 0 Cov.: 34 AF XY: 0.00000295 AC XY: 2 AN XY: 678650

African (AFR) AF: 0.00 AC: 0 AN: 28370

American (AMR) AF: 0.0000290 AC: 1 AN: 34534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24240

East Asian (EAS) AF: 0.00 AC: 0 AN: 32166

South Asian (SAS) AF: 0.00 AC: 0 AN: 77094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5590

European-Non Finnish (NFE) AF: 0.00000279 AC: 3 AN: 1073828

Other (OTH) AF: 0.00 AC: 0 AN: 56972

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

TMEM165-congenital disorder of glycosylation Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	15
DANN	Benign	0.46
DEOGEN2	Benign	0.025	.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.59	T;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.8	.;L
PhyloP100		0.12
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.65	N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0030	D;T
Sift4G	Pathogenic	0.0	D;T
Polyphen		0.0	.;B
Vest4		0.15
MutPred		0.27		Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);
MVP		0.21
MPC		0.93
ClinPred		0.15	T
GERP RS		1.6
PromoterAI		0.12	Neutral
Varity_R		0.021
gMVP		0.33
Mutation Taster		=82/18	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: rs1720719387; hg19: chr4-56262448;