rs116687212

Variant names:

• chr4-55396043-T-C
• rs116687212
• NM_018475.5:c.-147T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018475.5(TMEM165):​c.-147T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00939 in 555,812 control chromosomes in the GnomAD database, including 250 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.027 (209 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (41 hom.)
• Consequence: TMEM165 NM_018475.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0410
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0923 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM165	NM_018475.5	c.-147T>C		5_prime_UTR_variant	Exon 1 of 6	ENST00000381334.10	NP_060945.2
TMEM165	NR_073070.2	n.87T>C		non_coding_transcript_exon_variant	Exon 1 of 7
TMEM165	XM_011534394.4	c.-147T>C		5_prime_UTR_variant	Exon 1 of 6		XP_011532696.1
TMEM165	XM_017008412.2	c.-592T>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.-147T>C		5_prime_UTR_variant	Exon 1 of 6	1	NM_018475.5	ENSP00000370736.5

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4149 AN: 152012 Hom.: 209 Cov.: 32

Gnomad AFR AF: 0.0950

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0172

GnomAD4 exome AF: 0.00264 AC: 1065 AN: 403692 Hom.: 41 Cov.: 6 AF XY: 0.00202 AC XY: 412 AN XY: 203740

African (AFR) AF: 0.0955 AC: 810 AN: 8482

American (AMR) AF: 0.00790 AC: 53 AN: 6708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9466

East Asian (EAS) AF: 0.00 AC: 0 AN: 20840

South Asian (SAS) AF: 0.000242 AC: 3 AN: 12392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23204

Middle Eastern (MID) AF: 0.00246 AC: 4 AN: 1626

European-Non Finnish (NFE) AF: 0.000170 AC: 51 AN: 299644

Other (OTH) AF: 0.00675 AC: 144 AN: 21330

GnomAD4 genome AF: 0.0273 AC: 4153 AN: 152120 Hom.: 209 Cov.: 32 AF XY: 0.0262 AC XY: 1948 AN XY: 74360

African (AFR) AF: 0.0948 AC: 3937 AN: 41532

American (AMR) AF: 0.0104 AC: 159 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67966

Other (OTH) AF: 0.0170 AC: 36 AN: 2116

Alfa AF: 0.0262 Hom.: 21

Bravo AF: 0.0309

Asia WGS AF: 0.00376 AC: 13 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TMEM165-congenital disorder of glycosylation Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Sep 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.6
DANN	Benign	0.29
PhyloP100		-0.041
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

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: rs116687212; hg19: chr4-56262210;