19-46746071-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024301.5(FKRP):​c.-272G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000944 in 1,059,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 9.4e-7 (0 hom.)
• Consequence: FKRP NM_024301.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.763
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5	c.-272G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 4	ENST00000318584.10	NP_077277.1
FKRP	NM_024301.5	c.-272G>T		5_prime_UTR_variant	Exon 1 of 4	ENST00000318584.10	NP_077277.1
STRN4	NM_013403.3	c.282+78C>A		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>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 4	1	NM_024301.5	ENSP00000326570.4
FKRP	ENST00000318584.10	c.-272G>T		5_prime_UTR_variant	Exon 1 of 4	1	NM_024301.5	ENSP00000326570.4
STRN4	ENST00000263280.11	c.282+78C>A		intron_variant	Intron 1 of 17	1	NM_013403.3	ENSP00000263280.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 9.44e-7 AC: 1 AN: 1059494 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 515338

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.00000113 AC: 1 AN: 886480

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	20
DANN	Benign	0.93
PhyloP100		0.76
PromoterAI		-0.95	Under-expression

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;