4-55396286-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018475.5(TMEM165):c.97G>A(p.Ala33Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000294 in 1,528,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: TMEM165 NM_018475.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27135777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM165	NM_018475.5	c.97G>A	p.Ala33Thr	missense_variant	1/6	ENST00000381334.10
TMEM165	XM_011534394.4	c.97G>A	p.Ala33Thr	missense_variant	1/6
TMEM165	XM_017008412.2	c.-349G>A		5_prime_UTR_variant	1/8
TMEM165	NR_073070.2	n.330G>A		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM165	ENST00000381334.10	c.97G>A	p.Ala33Thr	missense_variant	1/6	1	NM_018475.5	P1
TMEM165	ENST00000506198.5	c.97G>A	p.Ala33Thr	missense_variant	1/3	2
TMEM165	ENST00000514070.1	n.36G>A		non_coding_transcript_exon_variant	1/2	2
TMEM165	ENST00000508404.5	c.97G>A	p.Ala33Thr	missense_variant, NMD_transcript_variant	1/7	2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000233 AC: 3 AN: 128532 Hom.: 0 AF XY: 0.0000276 AC XY: 2 AN XY: 72356

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000425

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000383

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000312 AC: 43 AN: 1376374 Hom.: 0 Cov.: 34 AF XY: 0.0000367 AC XY: 25 AN XY: 681008

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000567

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: 0.0000353

Gnomad4 OTH exome AF: 0.0000525

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74306

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000117 Hom.: 0

Bravo AF: 0.0000189

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

Invitae

Apr 05, 2023

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1401006). This variant has not been reported in the literature in individuals affected with TMEM165-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 33 of the TMEM165 protein (p.Ala33Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
Dann	Benign	0.75
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.76	T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.30	T
MutationTaster	Benign	0.56	D;N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.97	N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.69	.;P
Vest4		0.20
MutPred		0.13		Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MVP		0.48
MPC		0.77
ClinPred		0.20	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.082
gMVP		0.41

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: rs1021277116; hg19: chr4-56262453; COSMIC: COSV104696862; COSMIC: COSV104696862;