chr5-151467200-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_078483.4(SLC36A1):​c.421C>T​(p.Arg141Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000446 in 1,607,668 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R141S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00023 (3 hom.)
• Consequence: SLC36A1 NM_078483.4 missense, splice_region
• Scores: Splicing: ADA: 0.004932
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B: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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076419413).
• BP6: Variant 5-151467200-C-T is Benign according to our data. Variant chr5-151467200-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 709820.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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>T	p.Arg141Cys	missense splice_region	Exon 6 of 11	NP_510968.2
	SLC36A1	NM_001349740.2		c.337C>T	p.Arg113Cys	missense splice_region	Exon 7 of 12	NP_001336669.1
	SLC36A1	NM_001308150.2		c.421C>T	p.Arg141Cys	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>T	p.Arg141Cys	missense splice_region	Exon 6 of 11	ENSP00000243389.3	Q7Z2H8-1
	SLC36A1	ENST00000521925.5	TSL:1	c.421C>T	p.Arg141Cys	missense splice_region	Exon 6 of 10	ENSP00000430305.1	E7EW39
	SLC36A1	ENST00000429484.6	TSL:1	c.421C>T	p.Arg141Cys	missense splice_region	Exon 6 of 9	ENSP00000395640.2	Q7Z2H8-4

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 378 AN: 151560 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00876

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000719 AC: 179 AN: 248922 AF XY: 0.000505

Gnomad AFR exome AF: 0.00987

Gnomad AMR exome AF: 0.000410

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000234 AC: 340 AN: 1455990 Hom.: 3 Cov.: 31 AF XY: 0.000190 AC XY: 138 AN XY: 724554

African (AFR) AF: 0.00809 AC: 268 AN: 33128

American (AMR) AF: 0.000385 AC: 17 AN: 44142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

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

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85508

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

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5746

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1108254

Other (OTH) AF: 0.000582 AC: 35 AN: 60160

GnomAD4 genome AF: 0.00249 AC: 377 AN: 151678 Hom.: 1 Cov.: 31 AF XY: 0.00238 AC XY: 176 AN XY: 74064

African (AFR) AF: 0.00871 AC: 360 AN: 41326

American (AMR) AF: 0.000656 AC: 10 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 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: 0.0000441 AC: 3 AN: 67956

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.000338 Hom.: 0

Bravo AF: 0.00285

ESP6500AA AF: 0.0118 AC: 52

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000898 AC: 109

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.073
Sift	Benign	0.16	T
Sift4G	Benign	0.15	T
Polyphen		0.0040	B
Vest4		0.47
MVP		0.41
MPC		0.40
ClinPred		0.016	T
GERP RS		4.2
Varity_R		0.13
gMVP		0.37
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0049
dbscSNV1_RF	Benign	0.026
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: rs35204299; hg19: chr5-150846761; COSMIC: COSV99695470; COSMIC: COSV99695470;