4-55424053-A-G

Variant names:

• chr4-55424053-A-G
• rs534654
• NM_018475.5:c.793-485A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018475.5(TMEM165):​c.793-485A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.812 in 154,444 control chromosomes in the GnomAD database, including 51,158 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.81 (50414 hom., cov: 32)
  • Exomes 𝑓: 0.80 (744 hom.)
• Consequence: TMEM165 NM_018475.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.896
• Publications: 21 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

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.793-485A>G		intron	N/A	NP_060945.2
	TMEM165	NR_073070.2		n.1129-485A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM165	ENST00000381334.10	TSL:1 MANE Select	c.793-485A>G		intron	N/A	ENSP00000370736.5	Q9HC07-1
	TMEM165	ENST00000882548.1		c.793-485A>G		intron	N/A	ENSP00000552607.1
	TMEM165	ENST00000882549.1		c.793-485A>G		intron	N/A	ENSP00000552608.1

Frequencies

GnomAD3 genomes AF: 0.813 AC: 123573 AN: 152066 Hom.: 50383 Cov.: 32

Gnomad AFR AF: 0.797

Gnomad AMI AF: 0.640

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.805

Gnomad EAS AF: 0.979

Gnomad SAS AF: 0.956

Gnomad FIN AF: 0.840

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.798

Gnomad OTH AF: 0.816

GnomAD4 exome AF: 0.804 AC: 1817 AN: 2260 Hom.: 744 Cov.: 0 AF XY: 0.813 AC XY: 1026 AN XY: 1262

African (AFR) AF: 0.893 AC: 25 AN: 28

American (AMR) AF: 0.873 AC: 138 AN: 158

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 20 AN: 26

East Asian (EAS) AF: 0.967 AC: 29 AN: 30

South Asian (SAS) AF: 0.929 AC: 78 AN: 84

European-Finnish (FIN) AF: 0.871 AC: 54 AN: 62

Middle Eastern (MID) AF: 1.00 AC: 4 AN: 4

European-Non Finnish (NFE) AF: 0.788 AC: 1382 AN: 1754

Other (OTH) AF: 0.763 AC: 87 AN: 114

GnomAD4 genome AF: 0.813 AC: 123652 AN: 152184 Hom.: 50414 Cov.: 32 AF XY: 0.818 AC XY: 60894 AN XY: 74416

African (AFR) AF: 0.797 AC: 33062 AN: 41498

American (AMR) AF: 0.811 AC: 12401 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.805 AC: 2793 AN: 3470

East Asian (EAS) AF: 0.979 AC: 5066 AN: 5176

South Asian (SAS) AF: 0.956 AC: 4609 AN: 4822

European-Finnish (FIN) AF: 0.840 AC: 8895 AN: 10592

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.798 AC: 54266 AN: 68022

Other (OTH) AF: 0.819 AC: 1729 AN: 2112

Alfa AF: 0.804 Hom.: 222560

Bravo AF: 0.806

Asia WGS AF: 0.947 AC: 3296 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.1
DANN	Benign	0.49
PhyloP100		-0.90
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs534654; hg19: chr4-56290220;