19-17821329-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

Publications

43 publications found

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 Gene-Disease associations (from GenCC):

cryptorchidism
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

INSL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 1253265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.808 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
INSL3	NM_001265587.2 link	c.178A>G	p.Thr60Ala	missense_variant	Exon 1 of 3		NP_001252516.1

Ensembl

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

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

GnomAD2 exomes

AF:

0.649

AC:

91747

AN:

141390

AF XY:

0.648

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 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

African (AFR)

AF:

0.816

AC:

25732

AN:

31546

American (AMR)

AF:

0.630

AC:

22501

AN:

35716

Ashkenazi Jewish (ASJ)

AF:

0.603

AC:

15163

AN:

25144

East Asian (EAS)

AF:

0.661

AC:

23610

AN:

35708

South Asian (SAS)

AF:

0.627

AC:

49626

AN:

79210

European-Finnish (FIN)

AF:

0.720

AC:

33202

AN:

46086

Middle Eastern (MID)

AF:

0.693

AC:

3678

AN:

5308

European-Non Finnish (NFE)

AF:

0.642

AC:

692455

AN:

1078592

Other (OTH)

AF:

0.647

AC:

37468

AN:

57886

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

18368

36737

55105

73474

91842

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18536

37072

55608

74144

92680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.694

AC:

105696

AN:

152220

Hom.:

37213

Cov.:

AF XY:

0.696

AC XY:

51792

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.815

AC:

33866

AN:

41558

American (AMR)

AF:

0.634

AC:

9696

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.609

AC:

2113

AN:

3468

East Asian (EAS)

AF:

0.627

AC:

3231

AN:

5154

South Asian (SAS)

AF:

0.632

AC:

3053

AN:

4832

European-Finnish (FIN)

AF:

0.728

AC:

7731

AN:

10614

Middle Eastern (MID)

AF:

0.622

AC:

183

AN:

294

European-Non Finnish (NFE)

AF:

0.645

AC:

43867

AN:

67980

Other (OTH)

AF:

0.650

AC:

1375

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1717

3433

5150

6866

8583

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

818

1636

2454

3272

4090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

(source)

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

PhyloP100

-0.79

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

Vest4

0.037

ClinPred

0.0090

GERP RS

1.2

PromoterAI

-0.024

Neutral

(source)

Varity_R

0.048

gMVP

0.018

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over