4-55425387-GGA-CGG

Variant names:

• chr4-55425387-GGA-CGG
• NM_018475.5:c.910_912delGGAinsCGG
• TMEM165 p.Gly304Arg

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS1 PP2 PP3

The NM_018475.5(TMEM165):​c.910_912delGGAinsCGG​(p.Gly304Arg) variant causes a missense change involving the alteration of a 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM165 NM_018475.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.55
• 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]

TMEM165 Gene-Disease associations (from GenCC):

• TMEM165-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS1: Transcript NM_018475.5 (TMEM165) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018475.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM165	NM_018475.5	MANE Select	c.910_912delGGAinsCGG	p.Gly304Arg	missense	N/A	NP_060945.2
	TMEM165	NR_073070.2		n.1246_1248delGGAinsCGG		non_coding_transcript_exon	Exon 7 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM165	ENST00000381334.10	TSL:1 MANE Select	c.910_912delGGAinsCGG	p.Gly304Arg	missense	N/A	ENSP00000370736.5	Q9HC07-1
	TMEM165	ENST00000882548.1		c.910_912delGGAinsCGG	p.Gly304Arg	missense	N/A	ENSP00000552607.1
	TMEM165	ENST00000882549.1		c.910_912delGGAinsCGG	p.Gly304Arg	missense	N/A	ENSP00000552608.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.6

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-56291554;