4-55396207-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018475.5(TMEM165):c.18A>G(p.Pro6=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 1,436,182 control chromosomes in the GnomAD database, including 319,912 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39713 hom., cov: 33)
  • Exomes 𝑓: 0.66 (280199 hom.)
• Consequence: TMEM165 NM_018475.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.111

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 4-55396207-A-G is Benign according to our data. Variant chr4-55396207-A-G is described in ClinVar as [Benign]. Clinvar id is 193395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-55396207-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.111 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM165	NM_018475.5	c.18A>G	p.Pro6=	synonymous_variant	1/6	ENST00000381334.10
TMEM165	XM_011534394.4	c.18A>G	p.Pro6=	synonymous_variant	1/6
TMEM165	XM_017008412.2	c.-428A>G		5_prime_UTR_variant	1/8
TMEM165	NR_073070.2	n.251A>G		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM165	ENST00000381334.10	c.18A>G	p.Pro6=	synonymous_variant	1/6	1	NM_018475.5	P1
TMEM165	ENST00000506198.5	c.18A>G	p.Pro6=	synonymous_variant	1/3	2
TMEM165	ENST00000508404.5	c.18A>G	p.Pro6=	synonymous_variant, NMD_transcript_variant	1/7	2
TMEM165	ENST00000514070.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.718 AC: 108890 AN: 151698 Hom.: 39644 Cov.: 33

Gnomad AFR AF: 0.833

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.722

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.683

Gnomad SAS AF: 0.814

Gnomad FIN AF: 0.747

Gnomad MID AF: 0.605

Gnomad NFE AF: 0.645

Gnomad OTH AF: 0.682

GnomAD3 exomes AF: 0.705 AC: 50923 AN: 72280 Hom.: 18256 AF XY: 0.712 AC XY: 29924 AN XY: 42016

Gnomad AFR exome AF: 0.828

Gnomad AMR exome AF: 0.751

Gnomad ASJ exome AF: 0.660

Gnomad EAS exome AF: 0.636

Gnomad SAS exome AF: 0.807

Gnomad FIN exome AF: 0.734

Gnomad NFE exome AF: 0.635

Gnomad OTH exome AF: 0.649

GnomAD4 exome AF: 0.658 AC: 844722 AN: 1284374 Hom.: 280199 Cov.: 55 AF XY: 0.662 AC XY: 417873 AN XY: 631672

Gnomad4 AFR exome AF: 0.840

Gnomad4 AMR exome AF: 0.739

Gnomad4 ASJ exome AF: 0.663

Gnomad4 EAS exome AF: 0.756

Gnomad4 SAS exome AF: 0.803

Gnomad4 FIN exome AF: 0.733

Gnomad4 NFE exome AF: 0.636

Gnomad4 OTH exome AF: 0.677

GnomAD4 genome AF: 0.718 AC: 109013 AN: 151808 Hom.: 39713 Cov.: 33 AF XY: 0.725 AC XY: 53778 AN XY: 74206

Gnomad4 AFR AF: 0.833

Gnomad4 AMR AF: 0.722

Gnomad4 ASJ AF: 0.657

Gnomad4 EAS AF: 0.683

Gnomad4 SAS AF: 0.815

Gnomad4 FIN AF: 0.747

Gnomad4 NFE AF: 0.645

Gnomad4 OTH AF: 0.685

Alfa AF: 0.687 Hom.: 5594

Bravo AF: 0.715

Asia WGS AF: 0.765 AC: 2611 AN: 3412

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	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. -

TMEM165-congenital disorder of glycosylation Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Congenital disorder of glycosylation Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	9.3
Dann	Benign	0.19

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: rs1128141; hg19: chr4-56262374; COSMIC: COSV67262407; COSMIC: COSV67262407;