8-144509737-G-T

Variant names:

• chr8-144509737-G-T
• rs867219537
• NM_138431.3:c.404G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_138431.3(SLC33A2):​c.404G>T​(p.Gly135Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,800 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. G135D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SLC33A2 NM_138431.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.44
• Publications: 0 publications found

Genes affected

SLC33A2 (HGNC:25157): (major facilitator superfamily domain containing 3) Predicted to enable solute:proton symporter activity. Predicted to be involved in proton transmembrane transport. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138431.3. 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
	SLC33A2	NM_138431.3	MANE Select	c.404G>T	p.Gly135Val	missense	Exon 1 of 5	NP_612440.1	Q96ES6
	SLC33A2	NR_130120.2		n.668G>T		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFSD3	ENST00000301327.5	TSL:1 MANE Select	c.404G>T	p.Gly135Val	missense	Exon 1 of 5	ENSP00000301327.3	Q96ES6
	MFSD3	ENST00000883534.1		c.404G>T	p.Gly135Val	missense	Exon 1 of 5	ENSP00000553593.1
	MFSD3	ENST00000526749.1	TSL:2	n.119G>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1414800 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 701240

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

African (AFR) AF: 0.00 AC: 0 AN: 32484

American (AMR) AF: 0.00 AC: 0 AN: 39476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25466

East Asian (EAS) AF: 0.00 AC: 0 AN: 37274

South Asian (SAS) AF: 0.00 AC: 0 AN: 81634

European-Finnish (FIN) AF: 0.0000253 AC: 1 AN: 39596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094302

Other (OTH) AF: 0.00 AC: 0 AN: 58852

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.067	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.4
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.53		Loss of disorder (P = 0.0536)
MVP		0.80
MPC		0.22
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.77
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs867219537; hg19: chr8-145735120; COSMIC: COSV56742150; COSMIC: COSV56742150;