X-15639595-A-T

Variant names:

• chrX-15639595-A-T
• rs777199395
• NM_020665.6:c.479T>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_020665.6(CLTRN):​c.479T>A​(p.Leu160Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000373 in 1,207,639 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000071 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.000034 (0 hom. 17 hem.)
• Consequence: CLTRN NM_020665.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.91

Genes affected

CLTRN (HGNC:29437): (collectrin, amino acid transport regulator) This gene encodes a type 1 transmembrane protein that is important for trafficking amino acid transporters to the apical brush border of proximal tubules. The encoded protein binds to amino acid transporters and regulates their expression on the plasma membrane. It also plays a role in controlling insulin exocytosis by regulating formation of the SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptor) complex in pancreatic beta cells. The extracellular domain of the encoded protein may be cleaved and shed from the plasma membrane specifically in pancreatic beta cells. [provided by RefSeq, Jun 2013]

ENSG00000285602 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLTRN	NM_020665.6	c.479T>A	p.Leu160Gln	missense_variant	Exon 5 of 6	ENST00000380342.4	NP_065716.1
CLTRN	XM_017029680.2	c.323T>A	p.Leu108Gln	missense_variant	Exon 5 of 6		XP_016885169.1
CLTRN	XM_024452411.2	c.323T>A	p.Leu108Gln	missense_variant	Exon 5 of 6		XP_024308179.1
CLTRN	XM_017029681.2	c.204-11468T>A		intron_variant	Intron 3 of 3		XP_016885170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLTRN	ENST00000380342.4	c.479T>A	p.Leu160Gln	missense_variant	Exon 5 of 6	1	NM_020665.6	ENSP00000369699.3
ENSG00000285602	ENST00000649243.1	n.323T>A		non_coding_transcript_exon_variant	Exon 5 of 20			ENSP00000497489.1
CLTRN	ENST00000650271.1	c.323T>A	p.Leu108Gln	missense_variant	Exon 6 of 7			ENSP00000497814.1

Frequencies

GnomAD3 genomes AF: 0.0000714 AC: 8 AN: 112019 Hom.: 0 Cov.: 23 AF XY: 0.000146 AC XY: 5 AN XY: 34167

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000285

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.0000500 AC: 9 AN: 180079 Hom.: 0 AF XY: 0.0000463 AC XY: 3 AN XY: 64773

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.0000338 AC: 37 AN: 1095567 Hom.: 0 Cov.: 29 AF XY: 0.0000471 AC XY: 17 AN XY: 361129

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000860

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000935

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000262

Gnomad4 OTH exome AF: 0.0000652

GnomAD4 genome AF: 0.0000714 AC: 8 AN: 112072 Hom.: 0 Cov.: 23 AF XY: 0.000146 AC XY: 5 AN XY: 34230

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000284

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00131

Bravo AF: 0.000117

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.479T>A (p.L160Q) alteration is located in exon 5 (coding exon 5) of the TMEM27 gene. This alteration results from a T to A substitution at nucleotide position 479, causing the leucine (L) at amino acid position 160 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T;.
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.74	T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Uncertain	-0.010	T
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0080	D;.
Sift4G	Uncertain	0.058	T;.
Polyphen		0.97	D;.
Vest4		0.58
MutPred		0.43		Loss of stability (P = 0.043);.;
MVP		0.65
MPC		0.064
ClinPred		0.23	T
GERP RS		5.8
Varity_R		0.46
gMVP		0.44

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: rs777199395; hg19: chrX-15657718;