14-61037100-G-T

Variant names:

• chr14-61037100-G-T
• rs745806506
• NM_153811.3:c.524G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153811.3(SLC38A6):​c.524G>T​(p.Cys175Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. C175S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC38A6 NM_153811.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.27
• Publications: 0 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]

ENSG00000307460 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40639505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC38A6	NM_153811.3	c.524G>T	p.Cys175Phe	missense_variant	Exon 7 of 16	ENST00000267488.9	NP_722518.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC38A6	ENST00000267488.9	c.524G>T	p.Cys175Phe	missense_variant	Exon 7 of 16	1	NM_153811.3	ENSP00000267488.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458222 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725260

⚠️ 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: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 85742

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110002

Other (OTH) AF: 0.00 AC: 0 AN: 60240

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.15	.;T;T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.2	L;L;.;.
PhyloP100		3.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.018	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.87	P;P;.;.
Vest4		0.62
MVP		0.27
MPC		0.060
ClinPred		0.80	D
GERP RS		5.1
Varity_R		0.59
gMVP		0.81
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs745806506; hg19: chr14-61503818;