16-84022883-C-G

Variant names:

• chr16-84022883-C-G
• rs372929441
• NM_001080442.3:c.697G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001080442.3(SLC38A8):​c.697G>C​(p.Glu233Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,896 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E233G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC38A8 NM_001080442.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50
• Publications: 0 publications found

Genes affected

SLC38A8 (HGNC:32434): (solute carrier family 38 member 8) This gene encodes a putative sodium-dependent amino-acid/proton antiporter. The protein has eleven transmembrane domains, an extracellular N-terminus and an intracellular C-terminal tail. The protein is a member of the SLC38 sodium-coupled neutral amino acid transporter family of proteins. Mutations in this gene result in foveal hypoplasia with or without optic nerve misrouting and/or anterior segment dysgenesis. [provided by RefSeq, May 2014]

SLC38A8 Gene-Disease associations (from GenCC):

• foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-84022882-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 988804.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC38A8	NM_001080442.3	c.697G>C	p.Glu233Gln	missense_variant	Exon 7 of 11	ENST00000299709.8	NP_001073911.1
SLC38A8	XM_017022946.1	c.697G>C	p.Glu233Gln	missense_variant	Exon 8 of 12		XP_016878435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC38A8	ENST00000299709.8	c.697G>C	p.Glu233Gln	missense_variant	Exon 7 of 11	5	NM_001080442.3	ENSP00000299709.3
SLC38A8	ENST00000568178.1	c.697G>C	p.Glu233Gln	missense_variant	Exon 7 of 7	5		ENSP00000457737.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449896 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721030

African (AFR) AF: 0.00 AC: 0 AN: 32876

American (AMR) AF: 0.00 AC: 0 AN: 42326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25274

East Asian (EAS) AF: 0.00 AC: 0 AN: 39232

South Asian (SAS) AF: 0.00 AC: 0 AN: 84266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107280

Other (OTH) AF: 0.00 AC: 0 AN: 59938

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 30, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC38A8 c.697G>C (p.Glu233Gln) results in a conservative amino acid change located in the Amino acid transporter, transmembrane domain (IPR013057) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 234948 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.697G>C in individuals affected with Foveal Hypoplasia, Optic Nerve Decussation Defect, Anterior Segment Dysgenesis Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A different variant affecting the same codon has been classified as pathogenic by our lab (c.697G>A, p.Glu233Lys), supporting the critical relevance of codon 233 to SLC38A8 protein function. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M;.
PhyloP100		7.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.47
Sift	Benign	0.25	T;T
Sift4G	Benign	0.23	T;T
Polyphen		1.0	D;.
Vest4		0.74
MutPred		0.60		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.23
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.20
gMVP		0.85
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs372929441; hg19: chr16-84056488;