X-116442714-C-T

Variant names:

• chrX-116442714-C-T
• rs782131785
• NM_007231.5:c.374C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_007231.5(SLC6A14):​c.374C>T​(p.Ser125Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000218 in 1,145,708 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000022 (0 hom. 11 hem.)
• Consequence: SLC6A14 NM_007231.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51
• Publications: 1 publications found

Genes affected

SLC6A14 (HGNC:11047): (solute carrier family 6 member 14) This gene encodes a member of the solute carrier family 6. Members of this family are sodium and chloride dependent neurotransmitter transporters. The encoded protein transports both neutral and cationic amino acids. This protein may also function as a beta-alanine carrier. Mutations in this gene may be associated with X-linked obesity. A pseudogene of this gene is found on chromosome X.[provided by RefSeq, May 2010]

SLC6A14 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007231.5. 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
	SLC6A14	NM_007231.5	MANE Select	c.374C>T	p.Ser125Phe	missense	Exon 4 of 14	NP_009162.1	Q9UN76

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A14	ENST00000598581.3	TSL:1 MANE Select	c.374C>T	p.Ser125Phe	missense	Exon 4 of 14	ENSP00000470801.1	Q9UN76
	SLC6A14	ENST00000961161.1		c.374C>T	p.Ser125Phe	missense	Exon 4 of 14	ENSP00000631220.1
	SLC6A14	ENST00000905559.1		c.242C>T	p.Ser81Phe	missense	Exon 3 of 13	ENSP00000575618.1

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 110816 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000378

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000143 AC: 2 AN: 140197 AF XY: 0.0000438

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000294

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000222 AC: 23 AN: 1034892 Hom.: 0 Cov.: 26 AF XY: 0.0000336 AC XY: 11 AN XY: 327178

African (AFR) AF: 0.00 AC: 0 AN: 23032

American (AMR) AF: 0.00 AC: 0 AN: 23311

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17419

East Asian (EAS) AF: 0.00 AC: 0 AN: 27546

South Asian (SAS) AF: 0.00 AC: 0 AN: 43067

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39381

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3768

European-Non Finnish (NFE) AF: 0.0000283 AC: 23 AN: 813960

Other (OTH) AF: 0.00 AC: 0 AN: 43408

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 110816 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30463

American (AMR) AF: 0.00 AC: 0 AN: 10353

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2636

East Asian (EAS) AF: 0.00 AC: 0 AN: 3528

South Asian (SAS) AF: 0.00 AC: 0 AN: 2617

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5891

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.0000378 AC: 2 AN: 52931

Other (OTH) AF: 0.00 AC: 0 AN: 1481

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000612 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		3.5
PrimateAI	Uncertain	0.63	T
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.40
MutPred		0.49		Loss of glycosylation at S125 (P = 0.0722)
MVP		0.99
ClinPred		0.93	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.61
gMVP		0.88
Mutation Taster		=100/0	polymorphism

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: rs782131785; hg19: chrX-115573882;