4-55396238-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_018475.5(TMEM165):c.49C>T(p.Leu17Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,342,148 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: 0.0000015 ( 0 hom. )

Consequence

TMEM165
NM_018475.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.887

Publications

2 publications found

Variant links:

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]

TMEM165 links:

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

SRD5A3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.15728831).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM165	NM_018475.5 link	c.49C>T	p.Leu17Phe	missense_variant	Exon 1 of 6	ENST00000381334.10	NP_060945.2	Q9HC07-1
TMEM165	XM_011534394.4 link	c.49C>T	p.Leu17Phe	missense_variant	Exon 1 of 6		XP_011532696.1
TMEM165	NR_073070.2 link	n.282C>T		non_coding_transcript_exon_variant	Exon 1 of 7
TMEM165	XM_017008412.2 link	c.-397C>T		5_prime_UTR_variant	Exon 1 of 8		XP_016863901.1	Q9HC07-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM165	ENST00000381334.10 link	c.49C>T	p.Leu17Phe	missense_variant	Exon 1 of 6	1	NM_018475.5	ENSP00000370736.5		Q9HC07-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

99370

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000149

AC:

AN:

1342148

Hom.:

Cov.:

AF XY:

0.00000151

AC XY:

AN XY:

662980

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27414

American (AMR)

AF:

0.0000337

AC:

AN:

29664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23748

East Asian (EAS)

AF:

0.00

AC:

AN:

29530

South Asian (SAS)

AF:

0.00

AC:

AN:

74478

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35702

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5484

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1060366

Other (OTH)

AF:

0.0000179

AC:

AN:

55762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.49C>T (p.L17F) alteration is located in exon 1 (coding exon 1) of the TMEM165 gene. This alteration results from a C to T substitution at nucleotide position 49, causing the leucine (L) at amino acid position 17 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.040

.;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.51

T;T

M_CAP

Pathogenic

0.87

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.8

.;L

PhyloP100

0.89

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.19

N;N

REVEL

Benign

0.12

Sift

Benign

0.79

T;T

Sift4G

Pathogenic

0.0

D;T

Polyphen

0.077

.;B

Vest4

0.14

MutPred

0.29

Loss of helix (P = 0.079);Loss of helix (P = 0.079);

MVP

0.46

MPC

0.85

ClinPred

0.096

GERP RS

1.4

PromoterAI

0.018

Neutral

(source)

Varity_R

0.031

gMVP

0.26

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over