chrX-116441076-A-G

Variant names:

• chrX-116441076-A-G
• rs952099777
• NM_007231.5:c.325A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_007231.5(SLC6A14):​c.325A>G​(p.Arg109Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,139 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R109W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SLC6A14 NM_007231.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.03
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

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.325A>G	p.Arg109Gly	missense	Exon 3 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.325A>G	p.Arg109Gly	missense	Exon 3 of 14	ENSP00000470801.1	Q9UN76
	SLC6A14	ENST00000961161.1		c.325A>G	p.Arg109Gly	missense	Exon 3 of 14	ENSP00000631220.1
	SLC6A14	ENST00000961159.1		c.325A>G	p.Arg109Gly	missense	Exon 3 of 13	ENSP00000631218.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097139 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362607

African (AFR) AF: 0.00 AC: 0 AN: 26367

American (AMR) AF: 0.00 AC: 0 AN: 35183

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19353

East Asian (EAS) AF: 0.00 AC: 0 AN: 30148

South Asian (SAS) AF: 0.00 AC: 0 AN: 54088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841342

Other (OTH) AF: 0.00 AC: 0 AN: 46052

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.86	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.0
PrimateAI	Benign	0.41	T
Sift4G	Uncertain	0.016	D
Polyphen		0.39	B
Vest4		0.56
MutPred		0.72		Gain of catalytic residue at S106 (P = 0.0772)
MVP		0.75
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.42
gMVP		0.75
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.34		Position offset: 21

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

Other links and lift over

dbSNP: rs952099777; hg19: chrX-115572244;