19-17821329-T-C

Variant names:

Variant summary

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

The NM_005543.4(INSL3):c.178A>G(p.Thr60Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 1,547,416 control chromosomes in the GnomAD database, including 330,977 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.69 ( 37213 hom., cov: 35)

Exomes 𝑓: 0.65 ( 293764 hom. )

Consequence

INSL3
NM_005543.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.785

Variant links:

Genes affected

INSL3 (HGNC:6086): (insulin like 3) This gene encodes a member of the insulin-like hormone superfamily. The encoded protein is mainly produced in gonadal tissues. Studies of the mouse counterpart suggest that this gene may be involved in the development of urogenital tract and female fertility. This protein may also act as a hormone to regulate growth and differentiation of gubernaculum, and thus mediating intra-abdominal testicular descent. Mutations in this gene may lead to cryptorchidism. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

INSL3 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=1.494739E-6).

BP6

Variant 19-17821329-T-C is Benign according to our data. Variant chr19-17821329-T-C is described in ClinVar as [Benign]. Clinvar id is 1253265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-17821329-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSL3	NM_005543.4 link	c.178A>G	p.Thr60Ala	missense_variant	Exon 1 of 2	ENST00000317306.8	NP_005534.2	P51460-1
INSL3	NM_001265587.2 link	c.178A>G	p.Thr60Ala	missense_variant	Exon 1 of 3		NP_001252516.1	P51460-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
INSL3	ENST00000317306.8 link	c.178A>G	p.Thr60Ala	missense_variant	Exon 1 of 2	1	NM_005543.4	ENSP00000321724.6	P51460-1
INSL3	ENST00000379695.5 link	c.178A>G	p.Thr60Ala	missense_variant	Exon 1 of 3	1		ENSP00000369017.4	P51460-2
INSL3	ENST00000598577.1 link	c.175A>G	p.Thr59Ala	missense_variant	Exon 1 of 2	1		ENSP00000469309.1	M0QXQ3

Frequencies

GnomAD3 genomes

AF:

0.694

AC:

105597

AN:

152102

Hom.:

37162

Cov.:

show subpopulations

Gnomad AFR

AF:

0.815

Gnomad AMI

AF:

0.637

Gnomad AMR

AF:

0.634

Gnomad ASJ

AF:

0.609

Gnomad EAS

AF:

0.627

Gnomad SAS

AF:

0.631

Gnomad FIN

AF:

0.728

Gnomad MID

AF:

0.623

Gnomad NFE

AF:

0.645

Gnomad OTH

AF:

0.654

GnomAD3 exomes

AF:

0.649

AC:

91747

AN:

141390

Hom.:

29950

AF XY:

0.648

AC XY:

49431

AN XY:

76330

show subpopulations

Gnomad AFR exome

AF:

0.805

Gnomad AMR exome

AF:

0.630

Gnomad ASJ exome

AF:

0.606

Gnomad EAS exome

AF:

0.632

Gnomad SAS exome

AF:

0.624

Gnomad FIN exome

AF:

0.724

Gnomad NFE exome

AF:

0.640

Gnomad OTH exome

AF:

0.643

GnomAD4 exome

AF:

0.648

AC:

903435

AN:

1395196

Hom.:

293764

Cov.:

AF XY:

0.646

AC XY:

444951

AN XY:

688292

show subpopulations

Gnomad4 AFR exome

AF:

0.816

Gnomad4 AMR exome

AF:

0.630

Gnomad4 ASJ exome

AF:

0.603

Gnomad4 EAS exome

AF:

0.661

Gnomad4 SAS exome

AF:

0.627

Gnomad4 FIN exome

AF:

0.720

Gnomad4 NFE exome

AF:

0.642

Gnomad4 OTH exome

AF:

0.647

GnomAD4 genome

AF:

0.694

AC:

105696

AN:

152220

Hom.:

37213

Cov.:

AF XY:

0.696

AC XY:

51792

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.815

Gnomad4 AMR

AF:

0.634

Gnomad4 ASJ

AF:

0.609

Gnomad4 EAS

AF:

0.627

Gnomad4 SAS

AF:

0.632

Gnomad4 FIN

AF:

0.728

Gnomad4 NFE

AF:

0.645

Gnomad4 OTH

AF:

0.650

Alfa

AF:

0.657

Hom.:

10622

Bravo

AF:

0.693

TwinsUK

AF:

0.654

AC:

2425

ALSPAC

AF:

0.647

AC:

2492

ESP6500AA

AF:

0.830

AC:

3090

ESP6500EA

AF:

0.689

AC:

5029

ExAC

AF:

0.505

AC:

30766

Asia WGS

AF:

0.611

AC:

2125

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cryptorchidism

Benign:1

Aug 19, 2021

Genome-Nilou Lab

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

0.052

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.16

DANN

Benign

0.21

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0028

LIST_S2

Benign

0.14

T;T

MetaRNN

Benign

0.0000015

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-2.2

N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.89

N;N

REVEL

Benign

0.24

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.037

MPC

0.039

ClinPred

0.0090

GERP RS

1.2

Varity_R

0.048

gMVP

0.018

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