chr4-55396043-T-C

Position:

• chr4-55396043-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000381334.10(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. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (209 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (41 hom.)
• Consequence: TMEM165 ENST00000381334.10 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0410

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 4-55396043-T-C is Benign according to our data. Variant chr4-55396043-T-C is described in ClinVar as [Benign]. Clinvar id is 907295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	Protein	UniProt
TMEM165	NM_018475.5	c.-147T>C		5_prime_UTR_variant	1/6	ENST00000381334.10	NP_060945.2
TMEM165	XM_011534394.4	c.-147T>C		5_prime_UTR_variant	1/6		XP_011532696.1
TMEM165	XM_017008412.2	c.-592T>C		5_prime_UTR_variant	1/8		XP_016863901.1
TMEM165	NR_073070.2	n.87T>C		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM165	ENST00000381334.10	c.-147T>C		5_prime_UTR_variant	1/6	1	NM_018475.5	ENSP00000370736	P1
TMEM165	ENST00000506198.5	c.-147T>C		5_prime_UTR_variant	1/3	2		ENSP00000425449
TMEM165	ENST00000508404.5	c.-147T>C		5_prime_UTR_variant, NMD_transcript_variant	1/7	2		ENSP00000422639

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

Gnomad4 AFR exome AF: 0.0955

Gnomad4 AMR exome AF: 0.00790

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000242

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000170

Gnomad4 OTH exome AF: 0.00675

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

Gnomad4 AFR AF: 0.0948

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0228 Hom.: 18

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.6
DANN	Benign	0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs116687212; hg19: chr4-56262210;