11-93180825-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152313.4(SLC36A4):c.512T>C(p.Ile171Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC36A4 NM_152313.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.07

Genes affected

SLC36A4 (HGNC:19660): (solute carrier family 36 member 4) SLC36A4 belongs to the SLC36 family of amino acid transporters based on sequence similarity with other family members (e.g., SLC36A1; MIM 606561). SLC36 proteins contain about 500 amino acids and have 9 to 11 transmembrane domains. Unlike other SLC36 family members, which are proton-coupled amino acid transporters, SLC36A4 is a high-affinity/low-capacity non-proton-coupled amino acid transporter (Pillai and Meredith, 2011 [PubMed 21097500]).[supplied by OMIM, Feb 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC36A4	NM_152313.4	c.512T>C	p.Ile171Thr	missense_variant	6/11	ENST00000326402.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC36A4	ENST00000326402.9	c.512T>C	p.Ile171Thr	missense_variant	6/11	1	NM_152313.4	P1
SLC36A4	ENST00000529184.5	c.107T>C	p.Ile36Thr	missense_variant	6/11	2
SLC36A4	ENST00000534116.1	c.194T>C	p.Ile65Thr	missense_variant	3/7	3
SLC36A4	ENST00000524875.1	c.*147T>C		3_prime_UTR_variant, NMD_transcript_variant	6/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.512T>C (p.I171T) alteration is located in exon 6 (coding exon 6) of the SLC36A4 gene. This alteration results from a T to C substitution at nucleotide position 512, causing the isoleucine (I) at amino acid position 171 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.068	T;.;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	0.94	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.87	P;.;.
Vest4		0.84
MutPred		0.56		Loss of stability (P = 0.0075);.;.;
MVP		0.040
MPC		0.17
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.37
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs1861700448; hg19: chr11-92913991;