chr19-46777006-T-G

Position:

• chr19-46777006-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005628.3(SLC1A5):​c.1357A>C​(p.Ile453Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00838 in 1,613,820 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (11 hom., cov: 30)
  • Exomes 𝑓: 0.0086 (82 hom.)
• Consequence: SLC1A5 NM_005628.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.81

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009442538).
• BP6: Variant 19-46777006-T-G is Benign according to our data. Variant chr19-46777006-T-G is described in ClinVar as [Benign]. Clinvar id is 775581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC1A5	NM_005628.3	c.1357A>C	p.Ile453Leu	missense_variant	7/8	ENST00000542575.6	NP_005619.1
SLC1A5	NM_001145145.2	c.751A>C	p.Ile251Leu	missense_variant	6/7		NP_001138617.1
SLC1A5	NM_001145144.2	c.673A>C	p.Ile225Leu	missense_variant	7/8		NP_001138616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC1A5	ENST00000542575.6	c.1357A>C	p.Ile453Leu	missense_variant	7/8	1	NM_005628.3	ENSP00000444408.1

Frequencies

GnomAD3 genomes AF: 0.00610 AC: 927 AN: 151890 Hom.: 11 Cov.: 30

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00374

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.00171

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00952

Gnomad OTH AF: 0.00958

GnomAD3 exomes AF: 0.00741 AC: 1863 AN: 251308 Hom.: 9 AF XY: 0.00764 AC XY: 1038 AN XY: 135832

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.0234

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00666

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.00861 AC: 12591 AN: 1461814 Hom.: 82 Cov.: 31 AF XY: 0.00875 AC XY: 6363 AN XY: 727208

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00447

Gnomad4 ASJ exome AF: 0.0239

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00684

Gnomad4 FIN exome AF: 0.00169

Gnomad4 NFE exome AF: 0.00938

Gnomad4 OTH exome AF: 0.00849

GnomAD4 genome AF: 0.00609 AC: 926 AN: 152006 Hom.: 11 Cov.: 30 AF XY: 0.00576 AC XY: 428 AN XY: 74288

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00623

Gnomad4 FIN AF: 0.00171

Gnomad4 NFE AF: 0.00952

Gnomad4 OTH AF: 0.00948

Alfa AF: 0.0105 Hom.: 4

Bravo AF: 0.00664

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0119 AC: 102

ExAC AF: 0.00745 AC: 905

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0107

EpiControl AF: 0.0108

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T;.;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T;T;T;T
MetaRNN	Benign	0.0094	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.82	L;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.3	N;N;.;N
REVEL	Benign	0.062
Sift	Benign	0.20	T;T;.;T
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.0050	B;.;.;.
Vest4		0.23
MVP		0.52
MPC		0.63
ClinPred		0.010	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs79376478; hg19: chr19-47280263; COSMIC: COSV101314852; COSMIC: COSV101314852;