chr19-46746328-A-G

Variant names:

• chr19-46746328-A-G
• rs1427783096
• NM_013403.3:c.103T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_013403.3(STRN4):​c.103T>C​(p.Ser35Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,305,522 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: STRN4 NM_013403.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.545
• Publications: 0 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, Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.124203384).
• BS2: High AC in GnomAdExome4 at 46 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.103T>C	p.Ser35Pro	missense	Exon 1 of 18	NP_037535.2	Q9NRL3-1
	FKRP	NM_024301.5	MANE Select	c.-253+238A>G		intron	N/A	NP_077277.1	Q9H9S5
	STRN4	NM_001039877.2		c.103T>C	p.Ser35Pro	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.103T>C	p.Ser35Pro	missense	Exon 1 of 18	ENSP00000263280.4	Q9NRL3-1
	FKRP	ENST00000318584.10	TSL:1 MANE Select	c.-253+238A>G		intron	N/A	ENSP00000326570.4	Q9H9S5
	STRN4	ENST00000391910.7	TSL:5	c.103T>C	p.Ser35Pro	missense	Exon 1 of 18	ENSP00000375777.1	Q9NRL3-3

Frequencies

GnomAD3 genomes AF: 0.00000678 AC: 1 AN: 147564 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: 0.000203

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 46 AN: 1157958 Hom.: 0 Cov.: 34 AF XY: 0.0000302 AC XY: 17 AN XY: 563150

African (AFR) AF: 0.00 AC: 0 AN: 22442

American (AMR) AF: 0.00 AC: 0 AN: 8176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14496

East Asian (EAS) AF: 0.00181 AC: 45 AN: 24860

South Asian (SAS) AF: 0.00 AC: 0 AN: 44650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3244

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 967796

Other (OTH) AF: 0.0000216 AC: 1 AN: 46232

GnomAD4 genome AF: 0.00000678 AC: 1 AN: 147564 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 71968

African (AFR) AF: 0.00 AC: 0 AN: 40386

American (AMR) AF: 0.00 AC: 0 AN: 14958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.000203 AC: 1 AN: 4918

South Asian (SAS) AF: 0.00 AC: 0 AN: 4706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66538

Other (OTH) AF: 0.00 AC: 0 AN: 2042

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

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	0.058
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.55
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.040
Sift	Benign	0.031	D
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.19		Loss of phosphorylation at S35 (P = 0.0088)
MVP		0.26
MPC		0.94
ClinPred		0.23	T
GERP RS		0.75
PromoterAI		-0.042	Neutral
Varity_R		0.14
gMVP		0.18
Mutation Taster		=83/17	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: rs1427783096; hg19: chr19-47249585;