19-46720724-C-T

Variant names:

• chr19-46720724-C-T
• rs140848551
• NM_013403.3:c.2140G>A

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.2140G>A​(p.Val714Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000688 in 1,608,154 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00071 (2 hom.)
• Consequence: STRN4 NM_013403.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.26
• Publications: 4 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=0.12072092).
• BS2: High AC in GnomAd4 at 69 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRN4	NM_013403.3	c.2140G>A	p.Val714Met	missense_variant	Exon 17 of 18	ENST00000263280.11	NP_037535.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRN4	ENST00000263280.11	c.2140G>A	p.Val714Met	missense_variant	Exon 17 of 18	1	NM_013403.3	ENSP00000263280.4

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000415 AC: 102 AN: 245674 AF XY: 0.000458

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000782

Gnomad OTH exome AF: 0.000507

GnomAD4 exome AF: 0.000712 AC: 1037 AN: 1455826 Hom.: 2 Cov.: 30 AF XY: 0.000717 AC XY: 519 AN XY: 723692

African (AFR) AF: 0.000120 AC: 4 AN: 33346

American (AMR) AF: 0.000227 AC: 10 AN: 44112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39432

South Asian (SAS) AF: 0.000106 AC: 9 AN: 84984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5748

European-Non Finnish (NFE) AF: 0.000878 AC: 973 AN: 1108684

Other (OTH) AF: 0.000615 AC: 37 AN: 60142

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74484

African (AFR) AF: 0.000144 AC: 6 AN: 41582

American (AMR) AF: 0.000196 AC: 3 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000814 Hom.: 1

Bravo AF: 0.000533

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2161G>A (p.V721M) alteration is located in exon 17 (coding exon 17) of the STRN4 gene. This alteration results from a G to A substitution at nucleotide position 2161, causing the valine (V) at amino acid position 721 to be replaced by a methionine (M). 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	0.14
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T;.;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.9	M;.;.
PhyloP100		2.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.49
MVP		0.74
MPC		2.3
ClinPred		0.16	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.48
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140848551; hg19: chr19-47223981; COSMIC: COSV99354295; COSMIC: COSV99354295;