NM_013403.3:c.250G>A

Variant names:

• chr19-46746181-C-T
• rs755899946
• NM_013403.3:c.250G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_013403.3(STRN4):​c.250G>A​(p.Ala84Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,538,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A84V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: STRN4 NM_013403.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.718
• Publications: 1 publications found

Genes affected

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]

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]

FKRP Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy type 2I

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Genomics England PanelApp, Ambry Genetics
• muscular dystrophy-dystroglycanopathy type B5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• myopathy caused by variation in FKRP

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital muscular dystrophy with cerebellar involvement

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy without intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscle-eye-brain disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014166921).
• BS2: High AC in GnomAd4 at 22 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013403.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRN4	NM_013403.3	MANE Select	c.250G>A	p.Ala84Thr	missense	Exon 1 of 18	NP_037535.2	Q9NRL3-1
	FKRP	NM_024301.5	MANE Select	c.-253+91C>T		intron	N/A	NP_077277.1	Q9H9S5
	STRN4	NM_001039877.2		c.250G>A	p.Ala84Thr	missense	Exon 1 of 18	NP_001034966.1	Q9NRL3-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRN4	ENST00000263280.11	TSL:1 MANE Select	c.250G>A	p.Ala84Thr	missense	Exon 1 of 18	ENSP00000263280.4	Q9NRL3-1
	FKRP	ENST00000318584.10	TSL:1 MANE Select	c.-253+91C>T		intron	N/A	ENSP00000326570.4	Q9H9S5
	STRN4	ENST00000391910.7	TSL:5	c.250G>A	p.Ala84Thr	missense	Exon 1 of 18	ENSP00000375777.1	Q9NRL3-3

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151480 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00124

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000308 AC: 49 AN: 158834 AF XY: 0.000243

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00117

Gnomad NFE exome AF: 0.000493

Gnomad OTH exome AF: 0.000531

GnomAD4 exome AF: 0.000131 AC: 182 AN: 1386678 Hom.: 0 Cov.: 35 AF XY: 0.000112 AC XY: 77 AN XY: 688868

African (AFR) AF: 0.00 AC: 0 AN: 28680

American (AMR) AF: 0.00 AC: 0 AN: 37912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24220

East Asian (EAS) AF: 0.00 AC: 0 AN: 32214

South Asian (SAS) AF: 0.00 AC: 0 AN: 79698

European-Finnish (FIN) AF: 0.00106 AC: 41 AN: 38686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5534

European-Non Finnish (NFE) AF: 0.000115 AC: 125 AN: 1082526

Other (OTH) AF: 0.000280 AC: 16 AN: 57208

GnomAD4 genome AF: 0.000145 AC: 22 AN: 151590 Hom.: 0 Cov.: 30 AF XY: 0.000229 AC XY: 17 AN XY: 74098

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5078

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00124 AC: 13 AN: 10464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000133 AC: 9 AN: 67768

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000379 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000399 AC: 46

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.21	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L
PhyloP100		0.72
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.024
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.14	T
Polyphen		0.44	B
Vest4		0.14
MVP		0.36
MPC		0.40
ClinPred		0.077	T
GERP RS		0.93
PromoterAI		0.018	Neutral
Varity_R		0.18
gMVP		0.16
Mutation Taster		=100/0	polymorphism

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: rs755899946; hg19: chr19-47249438;