19-46775732-G-A

Variant names:

• chr19-46775732-G-A
• rs73940768
• NM_005628.3:c.1404C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_005628.3(SLC1A5):​c.1404C>T​(p.Thr468Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,613,770 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.010 (24 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (29 hom.)
• Consequence: SLC1A5 NM_005628.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.07

Genes affected

SLC1A5 (HGNC:10943): (solute carrier family 1 member 5) The SLC1A5 gene encodes a sodium-dependent neutral amino acid transporter that can act as a receptor for RD114/type D retrovirus (Larriba et al., 2001 [PubMed 11781704]).[supplied by OMIM, Jan 2011]

FKRP (HGNC:17997): (fukutin related protein) This gene encodes a protein which is targeted to the medial Golgi apparatus and is necessary for posttranslational modification of dystroglycan. Mutations in this gene have been associated with congenital muscular dystrophy, cognitive disability, and cerebellar cysts. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 19-46775732-G-A is Benign according to our data. Variant chr19-46775732-G-A is described in ClinVar as [Benign]. Clinvar id is 3049426.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-2.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0103 (1560/152190) while in subpopulation AFR AF= 0.0363 (1508/41514). AF 95% confidence interval is 0.0348. There are 24 homozygotes in gnomad4. There are 753 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC1A5	NM_005628.3	c.1404C>T	p.Thr468Thr	synonymous_variant	Exon 8 of 8	ENST00000542575.6	NP_005619.1
SLC1A5	NM_001145145.2	c.798C>T	p.Thr266Thr	synonymous_variant	Exon 7 of 7		NP_001138617.1
SLC1A5	NM_001145144.2	c.720C>T	p.Thr240Thr	synonymous_variant	Exon 8 of 8		NP_001138616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC1A5	ENST00000542575.6	c.1404C>T	p.Thr468Thr	synonymous_variant	Exon 8 of 8	1	NM_005628.3	ENSP00000444408.1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1560 AN: 152072 Hom.: 24 Cov.: 31

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

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: 0.0000294

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00296 AC: 735 AN: 248196 Hom.: 14 AF XY: 0.00214 AC XY: 288 AN XY: 134292

Gnomad AFR exome AF: 0.0416

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.000987

GnomAD4 exome AF: 0.00103 AC: 1505 AN: 1461580 Hom.: 29 Cov.: 34 AF XY: 0.000854 AC XY: 621 AN XY: 727070

Gnomad4 AFR exome AF: 0.0379

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00200

GnomAD4 genome AF: 0.0103 AC: 1560 AN: 152190 Hom.: 24 Cov.: 31 AF XY: 0.0101 AC XY: 753 AN XY: 74406

Gnomad4 AFR AF: 0.0363

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00576 Hom.: 4

Bravo AF: 0.0116

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

SLC1A5-related disorder Benign:1

Feb 14, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	4.6
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs73940768; hg19: chr19-47278989;