19-46723276-C-G

Variant names:

• chr19-46723276-C-G
• rs200300490
• NM_013403.3:c.1603G>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.1603G>C​(p.Val535Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000239 in 1,545,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: STRN4 NM_013403.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63
• 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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.073107034).
• BS2: High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRN4	NM_013403.3	c.1603G>C	p.Val535Leu	missense_variant	Exon 13 of 18	ENST00000263280.11	NP_037535.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRN4	ENST00000263280.11	c.1603G>C	p.Val535Leu	missense_variant	Exon 13 of 18	1	NM_013403.3	ENSP00000263280.4

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000172 AC: 25 AN: 145512 AF XY: 0.000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000283

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000248 AC: 345 AN: 1393260 Hom.: 0 Cov.: 32 AF XY: 0.000246 AC XY: 169 AN XY: 687564

African (AFR) AF: 0.00 AC: 0 AN: 31658

American (AMR) AF: 0.000279 AC: 10 AN: 35820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25142

East Asian (EAS) AF: 0.00 AC: 0 AN: 35840

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42882

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5504

European-Non Finnish (NFE) AF: 0.000297 AC: 321 AN: 1079252

Other (OTH) AF: 0.000207 AC: 12 AN: 57924

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74474

African (AFR) AF: 0.0000481 AC: 2 AN: 41574

American (AMR) AF: 0.000131 AC: 2 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000210 Hom.: 0

Bravo AF: 0.000185

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000481 AC: 4

ExAC AF: 0.000109 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 09, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1624G>C (p.V542L) alteration is located in exon 13 (coding exon 13) of the STRN4 gene. This alteration results from a G to C substitution at nucleotide position 1624, causing the valine (V) at amino acid position 542 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;T
Eigen	Benign	-0.082
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.073	T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	-0.20	N;.;.
PhyloP100		1.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Benign	0.27
Sift	Uncertain	0.015	D;D;D
Sift4G	Uncertain	0.032	D;D;D
Polyphen		0.21	B;.;.
Vest4		0.12
MutPred		0.71		.;Loss of sheet (P = 0.0817);.;
MVP		0.55
MPC		0.59
ClinPred		0.16	T
GERP RS		4.7
PromoterAI		-0.0052	Neutral
Varity_R		0.21
gMVP		0.36
Mutation Taster		=70/30	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: rs200300490; hg19: chr19-47226533;