chr5-151467200-C-A

Variant names:

• chr5-151467200-C-A
• rs35204299
• NM_078483.4:c.421C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_078483.4(SLC36A1):​c.421C>A​(p.Arg141Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000342 in 1,607,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. R141C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000073 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: SLC36A1 NM_078483.4 missense, splice_region
• Scores: Splicing: ADA: 0.002884
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68
• Publications: 4 publications found

Genes affected

SLC36A1 (HGNC:18761): (solute carrier family 36 member 1) This gene encodes a member of the eukaryote-specific amino acid/auxin permease (AAAP) 1 transporter family. The encoded protein functions as a proton-dependent, small amino acid transporter. This gene is clustered with related family members on chromosome 5q33.1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1756073).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_078483.4. 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
	SLC36A1	NM_078483.4	MANE Select	c.421C>A	p.Arg141Ser	missense splice_region	Exon 6 of 11	NP_510968.2
	SLC36A1	NM_001349740.2		c.337C>A	p.Arg113Ser	missense splice_region	Exon 7 of 12	NP_001336669.1
	SLC36A1	NM_001308150.2		c.421C>A	p.Arg141Ser	missense splice_region	Exon 6 of 11	NP_001295079.1	Q7Z2H8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC36A1	ENST00000243389.8	TSL:1 MANE Select	c.421C>A	p.Arg141Ser	missense splice_region	Exon 6 of 11	ENSP00000243389.3	Q7Z2H8-1
	SLC36A1	ENST00000521925.5	TSL:1	c.421C>A	p.Arg141Ser	missense splice_region	Exon 6 of 10	ENSP00000430305.1	E7EW39
	SLC36A1	ENST00000429484.6	TSL:1	c.421C>A	p.Arg141Ser	missense splice_region	Exon 6 of 9	ENSP00000395640.2	Q7Z2H8-4

Frequencies

GnomAD3 genomes AF: 0.0000726 AC: 11 AN: 151562 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000522 AC: 13 AN: 248922 AF XY: 0.0000520

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.000801

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000302 AC: 44 AN: 1455996 Hom.: 0 Cov.: 31 AF XY: 0.0000235 AC XY: 17 AN XY: 724556

African (AFR) AF: 0.0000906 AC: 3 AN: 33130

American (AMR) AF: 0.0000227 AC: 1 AN: 44142

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 85510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1108254

Other (OTH) AF: 0.000133 AC: 8 AN: 60162

GnomAD4 genome AF: 0.0000725 AC: 11 AN: 151680 Hom.: 0 Cov.: 31 AF XY: 0.0000675 AC XY: 5 AN XY: 74066

African (AFR) AF: 0.000145 AC: 6 AN: 41328

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67956

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000384 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.7
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.057
Sift	Benign	0.45	T
Sift4G	Benign	0.46	T
Polyphen		0.0030	B
Vest4		0.49
MutPred		0.46		Loss of MoRF binding (P = 0.0441)
MVP		0.42
MPC		0.34
ClinPred		0.030	T
GERP RS		4.2
Varity_R		0.22
gMVP		0.40
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0029
dbscSNV1_RF	Benign	0.068
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35204299; hg19: chr5-150846761;