rs3201779

Positions:

• chr19-46755417-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000318584.10(FKRP):​c.-34C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,582,586 control chromosomes in the GnomAD database, including 43,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2881 hom., cov: 33)
  • Exomes 𝑓: 0.23 (40135 hom.)
• Consequence: FKRP ENST00000318584.10 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.15

Genes affected

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 19-46755417-C-T is Benign according to our data. Variant chr19-46755417-C-T is described in ClinVar as [Benign]. Clinvar id is 96104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755417-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5	c.-34C>T		5_prime_UTR_variant	4/4	ENST00000318584.10	NP_077277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10	c.-34C>T		5_prime_UTR_variant	4/4	1	NM_024301.5	ENSP00000326570	P1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26349 AN: 152108 Hom.: 2878 Cov.: 33

Gnomad AFR AF: 0.0637

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.203

GnomAD3 exomes AF: 0.187 AC: 38453 AN: 206048 Hom.: 4343 AF XY: 0.194 AC XY: 22172 AN XY: 114158

Gnomad AFR exome AF: 0.0581

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.261

Gnomad EAS exome AF: 0.000551

Gnomad SAS exome AF: 0.195

Gnomad FIN exome AF: 0.211

Gnomad NFE exome AF: 0.251

Gnomad OTH exome AF: 0.210

GnomAD4 exome AF: 0.229 AC: 327436 AN: 1430360 Hom.: 40135 Cov.: 31 AF XY: 0.229 AC XY: 162548 AN XY: 710476

Gnomad4 AFR exome AF: 0.0568

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.258

Gnomad4 EAS exome AF: 0.000569

Gnomad4 SAS exome AF: 0.195

Gnomad4 FIN exome AF: 0.214

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.208

GnomAD4 genome AF: 0.173 AC: 26351 AN: 152226 Hom.: 2881 Cov.: 33 AF XY: 0.171 AC XY: 12729 AN XY: 74438

Gnomad4 AFR AF: 0.0635

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.268

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.177

Gnomad4 FIN AF: 0.210

Gnomad4 NFE AF: 0.247

Gnomad4 OTH AF: 0.200

Alfa AF: 0.218 Hom.: 1102

Bravo AF: 0.163

Asia WGS AF: 0.0690 AC: 240 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 15, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive limb-girdle muscular dystrophy type 2I Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Muscular dystrophy-dystroglycanopathy type B5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.0
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs3201779; hg19: chr19-47258674; COSMIC: COSV59358546; COSMIC: COSV59358546;