chr14-61030445-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_153811.3(SLC38A6):​c.404C>G​(p.Ala135Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000025 in 1,599,240 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). 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: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC38A6 NM_153811.3 missense, splice_region
• Scores: Splicing: ADA: 0.9215
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>G	p.Ala135Gly	missense splice_region	Exon 6 of 16	NP_722518.2	Q8IZM9-1
	SLC38A6	NM_001172702.2		c.404C>G	p.Ala135Gly	missense splice_region	Exon 6 of 17	NP_001166173.1	Q8IZM9-2
	SLC38A6	NR_033344.2		n.746C>G		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>G	p.Ala135Gly	missense splice_region	Exon 6 of 16	ENSP00000267488.4	Q8IZM9-1
	SLC38A6	ENST00000354886.6	TSL:1	c.404C>G	p.Ala135Gly	missense splice_region	Exon 6 of 17	ENSP00000346959.2	Q8IZM9-2
	SLC38A6	ENST00000451406.5	TSL:1	c.389C>G	p.Ala130Gly	missense splice_region	Exon 6 of 17	ENSP00000395851.1	A0A0C4DG39

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 33

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00 AC: 0 AN: 241442 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447152 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720140

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

American (AMR) AF: 0.0000472 AC: 2 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: 0.00 AC: 0 AN: 1104860

Other (OTH) AF: 0.0000167 AC: 1 AN: 59802

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74288

⚠️ 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: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

⚠️ 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: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

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	Uncertain	0.41
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.039	D
Polyphen		1.0	D
Vest4		0.72
MVP		0.32
MPC		0.13
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.86
gMVP		0.65
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Benign	0.65
SpliceAI score (max)		0.030		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;