Genetic Variant TMEM165:p.Gly9Gly (chr4-55396216-C-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_018475.5(TMEM165):c.27C>G(p.Gly9Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TMEM165
NM_018475.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.25

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 4-55396216-C-G is Benign according to our data. Variant chr4-55396216-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 386518.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.25 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM165	NM_018475.5 link	c.27C>G	p.Gly9Gly	synonymous_variant	Exon 1 of 6	ENST00000381334.10	NP_060945.2	Q9HC07-1
TMEM165	XM_011534394.4 link	c.27C>G	p.Gly9Gly	synonymous_variant	Exon 1 of 6		XP_011532696.1
TMEM165	NR_073070.2 link	n.260C>G		non_coding_transcript_exon_variant	Exon 1 of 7
TMEM165	XM_017008412.2 link	c.-419C>G		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.27C>G	p.Gly9Gly	synonymous_variant	Exon 1 of 6	1	NM_018475.5	ENSP00000370736.5		Q9HC07-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

77386

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000154

AC:

AN:

1302398

Hom.:

Cov.:

AF XY:

0.00000312

AC XY:

AN XY:

641506

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26680

American (AMR)

AF:

0.00

AC:

AN:

24906

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22878

East Asian (EAS)

AF:

0.00

AC:

AN:

27842

South Asian (SAS)

AF:

0.00

AC:

AN:

68424

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5108

European-Non Finnish (NFE)

AF:

0.00000192

AC:

AN:

1039254

Other (OTH)

AF:

0.00

AC:

AN:

53962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 18, 2016

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.54

PhyloP100

1.3

PromoterAI

-0.068

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.4

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