4-55396206-CA-GG

Variant names:

• chr4-55396206-CA-GG
• NM_018475.5:c.17_18delCAinsGG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_018475.5(TMEM165):​c.17_18delCAinsGG​(p.Pro6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P6P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM165 NM_018475.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.111
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.3658 (below the threshold of 3.09). Trascript score misZ: 0.68834 (below the threshold of 3.09). GenCC associations: The gene is linked to TMEM165-congenital disorder of glycosylation.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM165	NM_018475.5	c.17_18delCAinsGG	p.Pro6Arg	missense_variant		ENST00000381334.10	NP_060945.2
TMEM165	XM_011534394.4	c.17_18delCAinsGG	p.Pro6Arg	missense_variant			XP_011532696.1
TMEM165	NR_073070.2	n.250_251delCAinsGG		non_coding_transcript_exon_variant	Exon 1 of 7
TMEM165	XM_017008412.2	c.-429_-428delCAinsGG		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.17_18delCAinsGG	p.Pro6Arg	missense_variant		1	NM_018475.5	ENSP00000370736.5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

TMEM165-congenital disorder of glycosylation Uncertain:1

Jun 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 6 of the TMEM165 protein (p.Pro6Arg). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with TMEM165-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.11

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr4-56262373;