14-61030445-C-T

Variant names:

• chr14-61030445-C-T
• rs750915264
• NM_153811.3:c.404C>T

Variant summary

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

The NM_153811.3(SLC38A6):​c.404C>T​(p.Ala135Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,447,152 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. 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. A135D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC38A6 NM_153811.3 missense, splice_region
• Scores: Splicing: ADA: 0.9772
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.69
• Publications: 1 publications found

Genes affected

SLC38A6 (HGNC:19863): (solute carrier family 38 member 6) Predicted to enable L-glutamine transmembrane transporter activity. Predicted to be involved in amino acid transmembrane transport and glutamine transport. Predicted to be located in plasma membrane. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153811.3. 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
	SLC38A6	NM_153811.3	MANE Select	c.404C>T	p.Ala135Val	missense splice_region	Exon 6 of 16	NP_722518.2	Q8IZM9-1
	SLC38A6	NM_001172702.2		c.404C>T	p.Ala135Val	missense splice_region	Exon 6 of 17	NP_001166173.1	Q8IZM9-2
	SLC38A6	NR_033344.2		n.746C>T		splice_region non_coding_transcript_exon	Exon 6 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC38A6	ENST00000267488.9	TSL:1 MANE Select	c.404C>T	p.Ala135Val	missense splice_region	Exon 6 of 16	ENSP00000267488.4	Q8IZM9-1
	SLC38A6	ENST00000354886.6	TSL:1	c.404C>T	p.Ala135Val	missense splice_region	Exon 6 of 17	ENSP00000346959.2	Q8IZM9-2
	SLC38A6	ENST00000451406.5	TSL:1	c.389C>T	p.Ala130Val	missense splice_region	Exon 6 of 17	ENSP00000395851.1	A0A0C4DG39

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447152 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 2 AN XY: 720140

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

African (AFR) AF: 0.00 AC: 0 AN: 32654

American (AMR) AF: 0.00 AC: 0 AN: 42334

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25662

East Asian (EAS) AF: 0.00 AC: 0 AN: 39494

South Asian (SAS) AF: 0.00 AC: 0 AN: 83738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5484

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1104860

Other (OTH) AF: 0.00 AC: 0 AN: 59802

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.33
Sift	Benign	0.057	T
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.81
MVP		0.34
MPC		0.13
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.89
gMVP		0.73
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.050		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: rs750915264; hg19: chr14-61497163;