chr4-55396238-C-T

Variant names:

• chr4-55396238-C-T
• rs1310849519
• NM_018475.5:c.49C>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.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. 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: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TMEM165 NM_018475.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.887

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=0.15728831).

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM165	ENST00000381334.10	c.49C>T	p.Leu17Phe	missense_variant	Exon 1 of 6	1	NM_018475.5	ENSP00000370736.5
TMEM165	ENST00000506198.5	c.49C>T	p.Leu17Phe	missense_variant	Exon 1 of 3	2		ENSP00000425449.1
TMEM165	ENST00000508404.5	n.49C>T		non_coding_transcript_exon_variant	Exon 1 of 7	2		ENSP00000422639.1
TMEM165	ENST00000514070.1	n.-13C>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1342148 Hom.: 0 Cov.: 34 AF XY: 0.00000151 AC XY: 1 AN XY: 662980

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000337

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: 0.00

Gnomad4 OTH exome AF: 0.0000179

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.72
DEOGEN2	Benign	0.040	.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.51	T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.8	.;L
PrimateAI	Pathogenic	0.86	D
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	T
GERP RS		1.4
Varity_R		0.031
gMVP		0.26

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

LitVar

Other links and lift over

dbSNP: rs1310849519; hg19: chr4-56262405; COSMIC: COSV104430476; COSMIC: COSV104430476;