chr16-87832995-A-G

Variant names:

• chr16-87832995-A-G
• rs2054951814
• NM_003486.7:c.1499T>C

Variant summary

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

The NM_003486.7(SLC7A5):​c.1499T>C​(p.Met500Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,620 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M500K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC7A5 NM_003486.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.88
• Publications: 0 publications found

Genes affected

SLC7A5 (HGNC:11063): (solute carrier family 7 member 5) Enables L-leucine transmembrane transporter activity; L-tryptophan transmembrane transporter activity; and thyroid hormone transmembrane transporter activity. Involved in carboxylic acid transport; thyroid hormone transport; and xenobiotic transport. Located in cytosol; intracellular membrane-bounded organelle; and plasma membrane. Is integral component of membrane. Part of amino acid transport complex; apical plasma membrane; and microvillus membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLC7A5 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics

SLC7A5-AS1 (HGNC:58301):

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_003486.7. 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
	SLC7A5	NM_003486.7	MANE Select	c.1499T>C	p.Met500Thr	missense	Exon 10 of 10	NP_003477.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC7A5	ENST00000261622.5	TSL:1 MANE Select	c.1499T>C	p.Met500Thr	missense	Exon 10 of 10	ENSP00000261622.4	Q01650
	SLC7A5	ENST00000565644.6	TSL:1	c.701T>C	p.Met234Thr	missense	Exon 10 of 10	ENSP00000454323.1	A0A0C4DGL4
	SLC7A5	ENST00000850914.1		c.1553T>C	p.Met518Thr	missense	Exon 10 of 10	ENSP00000520997.1	A0ABJ7H8K0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461620 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727128

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

African (AFR) AF: 0.0000896 AC: 3 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111914

Other (OTH) AF: 0.00 AC: 0 AN: 60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00793067), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	23
DANN	Benign	0.81
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.049
Eigen_PC	Benign	0.077
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.056	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.61
Sift	Benign	0.11	T
Sift4G	Benign	0.081	T
Polyphen		0.049	B
Vest4		0.53
MutPred		0.67		Loss of stability (P = 0.057)
MVP		0.66
MPC		1.0
ClinPred		0.79	D
GERP RS		5.2
Varity_R		0.68
gMVP		0.84
Mutation Taster		=6/94	disease causing

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: rs2054951814; hg19: chr16-87866601;