chr16-84022873-A-T

Variant names:

• chr16-84022873-A-T
• rs587777254
• NM_001080442.3:c.707T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001080442.3(SLC38A8):​c.707T>A​(p.Val236Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V236I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC38A8 NM_001080442.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.87
• Publications: 4 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001080442.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 16-84022873-A-T is Pathogenic according to our data. Variant chr16-84022873-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 125443.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.707T>A	p.Val236Asp	missense_variant	Exon 7 of 11	ENST00000299709.8	NP_001073911.1
SLC38A8	XM_017022946.1	c.707T>A	p.Val236Asp	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.707T>A	p.Val236Asp	missense_variant	Exon 7 of 11	5	NM_001080442.3	ENSP00000299709.3
SLC38A8	ENST00000568178.1	c.707T>A	p.Val236Asp	missense_variant	Exon 7 of 7	5		ENSP00000457737.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

FOVEAL HYPOPLASIA 2 WITH OPTIC NERVE MISROUTING AND ANTERIOR SEGMENT DYSGENESIS Pathogenic:1

Dec 05, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.34	T;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.9	M;.
PhyloP100		8.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.3	D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.84		Gain of disorder (P = 0.1019);Gain of disorder (P = 0.1019);
MVP		0.31
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.94
gMVP		0.92
Mutation Taster		=60/40	disease causing (ClinVar)

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: rs587777254; hg19: chr16-84056478;