Genetic Variant SLC45A1:p.Arg176Gly (chr1-8325853-C-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_001080397.3(SLC45A1):c.526C>G(p.Arg176Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R176W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC45A1
NM_001080397.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.44

Publications

0 publications found

Variant links:

Genes affected

SLC45A1 (HGNC:17939): (solute carrier family 45 member 1) This gene was isolated initially from a region on chromosome 1p that is frequently deleted in human neuroblastoma, although no causal relationship has since been demonstrated. The encoded protein belongs to the glycoside-pentoside-hexuronide cation symporter transporter family and may play a role in glucose uptake. [provided by RefSeq, Mar 2014]

SLC45A1 Gene-Disease associations (from GenCC):

intellectual developmental disorder with neuropsychiatric features
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC45A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-8325853-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 428599.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC45A1	NM_001080397.3 link	c.526C>G	p.Arg176Gly	missense_variant	Exon 4 of 9	ENST00000471889.7	NP_001073866.3	Q9Y2W3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC45A1	ENST00000471889.7 link	c.526C>G	p.Arg176Gly	missense_variant	Exon 4 of 9	5	NM_001080397.3	ENSP00000418096.3		Q9Y2W3
SLC45A1	ENST00000289877.8 link	c.526C>G	p.Arg176Gly	missense_variant	Exon 3 of 8	1		ENSP00000289877.8		A0A2H2EQP0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.099

Eigen_PC

Benign

-0.00037

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.88

D;D

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

0.57

PhyloP100

2.4

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.32

.;N

REVEL

Pathogenic

0.68

Sift

Benign

0.23

.;T

Sift4G

Uncertain

0.053

T;T

Vest4

0.74

MutPred

0.58

.;Loss of methylation at R176 (P = 0.0158);

MVP

0.93

MPC

0.99

ClinPred

0.77

GERP RS

0.15

Varity_R

0.14

gMVP

0.84

Mutation Taster

=27/73

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over