4-55424270-T-C

Variant names:

• chr4-55424270-T-C
• rs6858749
• NM_018475.5:c.793-268T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018475.5(TMEM165):​c.793-268T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 435,004 control chromosomes in the GnomAD database, including 60,625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (17762 hom., cov: 33)
  • Exomes 𝑓: 0.54 (42863 hom.)
• Consequence: TMEM165 NM_018475.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.74
• Publications: 12 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 4-55424270-T-C is Benign according to our data. Variant chr4-55424270-T-C is described in ClinVar as Benign. ClinVar VariationId is 1242762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.858 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM165	NM_018475.5	MANE Select	c.793-268T>C		intron	N/A	NP_060945.2
	TMEM165	NR_073070.2		n.1129-268T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM165	ENST00000381334.10	TSL:1 MANE Select	c.793-268T>C		intron	N/A	ENSP00000370736.5
	TMEM165	ENST00000515591.1	TSL:2	n.1157T>C		non_coding_transcript_exon	Exon 1 of 2
	TMEM165	ENST00000608091.1	TSL:3	c.301-268T>C		intron	N/A	ENSP00000476531.1

Frequencies

GnomAD3 genomes AF: 0.462 AC: 70273 AN: 151942 Hom.: 17758 Cov.: 33

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.880

Gnomad SAS AF: 0.584

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.517

Gnomad OTH AF: 0.493

GnomAD4 exome AF: 0.539 AC: 152445 AN: 282944 Hom.: 42863 Cov.: 0 AF XY: 0.541 AC XY: 79994 AN XY: 147750

African (AFR) AF: 0.244 AC: 1928 AN: 7890

American (AMR) AF: 0.560 AC: 5210 AN: 9298

Ashkenazi Jewish (ASJ) AF: 0.581 AC: 5346 AN: 9200

East Asian (EAS) AF: 0.842 AC: 15197 AN: 18044

South Asian (SAS) AF: 0.580 AC: 14672 AN: 25290

European-Finnish (FIN) AF: 0.491 AC: 8747 AN: 17802

Middle Eastern (MID) AF: 0.594 AC: 803 AN: 1352

European-Non Finnish (NFE) AF: 0.516 AC: 91278 AN: 176790

Other (OTH) AF: 0.536 AC: 9264 AN: 17278

GnomAD4 genome AF: 0.462 AC: 70272 AN: 152060 Hom.: 17762 Cov.: 33 AF XY: 0.467 AC XY: 34727 AN XY: 74328

African (AFR) AF: 0.263 AC: 10926 AN: 41478

American (AMR) AF: 0.541 AC: 8261 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 1969 AN: 3472

East Asian (EAS) AF: 0.880 AC: 4541 AN: 5162

South Asian (SAS) AF: 0.583 AC: 2810 AN: 4822

European-Finnish (FIN) AF: 0.483 AC: 5100 AN: 10564

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.517 AC: 35108 AN: 67968

Other (OTH) AF: 0.498 AC: 1051 AN: 2112

Alfa AF: 0.496 Hom.: 4778

Bravo AF: 0.461

Asia WGS AF: 0.665 AC: 2313 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.12
DANN	Benign	0.37
PhyloP100		-1.7
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: rs6858749; hg19: chr4-56290437;