19-46746071-G-A

Variant names:

• chr19-46746071-G-A
• rs1555735545
• NM_024301.5:c.-272G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_024301.5(FKRP):​c.-272G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FKRP NM_024301.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.763
• Publications: 1 publications found

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]

STRN4 (HGNC:15721): (striatin 4) Enables armadillo repeat domain binding activity and protein phosphatase 2A binding activity. Part of FAR/SIN/STRIPAK complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-46746071-G-A is Pathogenic according to our data. Variant chr19-46746071-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522865.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5	c.-272G>A		5_prime_UTR_variant	Exon 1 of 4	ENST00000318584.10	NP_077277.1
STRN4	NM_013403.3	c.282+78C>T		intron_variant	Intron 1 of 17	ENST00000263280.11	NP_037535.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10	c.-272G>A		5_prime_UTR_variant	Exon 1 of 4	1	NM_024301.5	ENSP00000326570.4
STRN4	ENST00000263280.11	c.282+78C>T		intron_variant	Intron 1 of 17	1	NM_013403.3	ENSP00000263280.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1059496 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 515342

African (AFR) AF: 0.00 AC: 0 AN: 19798

American (AMR) AF: 0.00 AC: 0 AN: 7178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12408

East Asian (EAS) AF: 0.00 AC: 0 AN: 22418

South Asian (SAS) AF: 0.00 AC: 0 AN: 43354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2952

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 886482

Other (OTH) AF: 0.00 AC: 0 AN: 41492

GnomAD4 genome Cov.: 30

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jan 11, 2017

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Aug 01, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Benign	0.95
PhyloP100		0.76
PromoterAI		-0.94	Under-expression
Mutation Taster		=39/261	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555735545; hg19: chr19-47249328;