Genetic Variant INSL4:p.Thr133Asn (chr9-5233855-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002195.2(INSL4):c.398C>A(p.Thr133Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,611,938 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 70 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 72 hom. )

Consequence

INSL4
NM_002195.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.53

Variant links:

Genes affected

INSL4 (HGNC:6087): (insulin like 4) INSL4 encodes the insulin-like 4 protein, a member of the insulin superfamily. INSL4 encodes a precursor that undergoes post-translational cleavage to produce 3 polypeptide chains, A-C, that form tertiary structures composed of either all three chains, or just the A and B chains. Expression of INSL4 products occurs within the early placental cytotrophoblast and syncytiotrophoblast. [provided by RefSeq, Jul 2008]

INSL4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026692748).

BP6

Variant 9-5233855-C-A is Benign according to our data. Variant chr9-5233855-C-A is described in ClinVar as [Benign]. Clinvar id is 792121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSL4	NM_002195.2 link	c.398C>A	p.Thr133Asn	missense_variant	Exon 2 of 2	ENST00000239316.4	NP_002186.1	Q14641

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSL4	ENST00000239316.4 link	c.398C>A	p.Thr133Asn	missense_variant	Exon 2 of 2	1	NM_002195.2	ENSP00000239316.4		Q14641

Frequencies

GnomAD3 genomes

AF:

0.0175

AC:

2670

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0590

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0114

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.00446

AC:

1116

AN:

250104

Hom.:

AF XY:

0.00353

AC XY:

477

AN XY:

135138

show subpopulations

Gnomad AFR exome

AF:

0.0607

Gnomad AMR exome

AF:

0.00293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000709

Gnomad OTH exome

AF:

0.00296

GnomAD4 exome

AF:

0.00175

AC:

2557

AN:

1459660

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

1114

AN XY:

726268

show subpopulations

Gnomad4 AFR exome

AF:

0.0615

Gnomad4 AMR exome

AF:

0.00392

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.00436

GnomAD4 genome

AF:

0.0176

AC:

2683

AN:

152278

Hom.:

Cov.:

AF XY:

0.0175

AC XY:

1300

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0592

Gnomad4 AMR

AF:

0.0114

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.00390

Hom.:

Bravo

AF:

0.0203

ESP6500AA

AF:

0.0601

AC:

265

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00542

AC:

658

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.57

CADD

Benign

1.1

DANN

Benign

0.80

DEOGEN2

Benign

0.016

Eigen

Benign

-0.81

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.40

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.83

REVEL

Benign

0.24

Sift

Benign

0.34

Sift4G

Benign

0.68

Polyphen

0.99

Vest4

0.075

MVP

0.58

MPC

0.0033

ClinPred

0.0082

GERP RS

-1.0

Varity_R

0.048

gMVP

0.087

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over