chr19-17816945-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM5BP4BP6BS1BS2_Supporting

The NM_005543.4(INSL3):c.305G>A(p.Arg102His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000491 in 1,614,046 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00051 ( 6 hom. )

Consequence

INSL3
NM_005543.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:1

Conservation

PhyloP100: 0.258

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 was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-17816946-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14831.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.3963346).

BP6

Variant 19-17816945-C-T is Benign according to our data. Variant chr19-17816945-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14832.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}. Variant chr19-17816945-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00051 (745/1461834) while in subpopulation SAS AF = 0.00352 (304/86258). AF 95% confidence interval is 0.0032. There are 6 homozygotes in GnomAdExome4. There are 445 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position FAILED quality control check.

BS2

High AC in GnomAd4 at 47 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSL3	NM_005543.4 link	c.305G>A	p.Arg102His	missense_variant	Exon 2 of 2	ENST00000317306.8	NP_005534.2	P51460-1
INSL3	NM_001265587.2 link	c.400G>A	p.Ala134Thr	missense_variant	Exon 3 of 3		NP_001252516.1	P51460-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
INSL3	ENST00000317306.8 link	c.305G>A	p.Arg102His	missense_variant	Exon 2 of 2	1	NM_005543.4	ENSP00000321724.6	P51460-1
INSL3	ENST00000379695.5 link	c.400G>A	p.Ala134Thr	missense_variant	Exon 3 of 3	1		ENSP00000369017.4	P51460-2
INSL3	ENST00000598577 link	c.*111G>A		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000469309.1	M0QXQ3

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000689

AC:

173

AN:

251090

AF XY:

0.000942

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000485

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000510

AC:

745

AN:

1461834

Hom.:

Cov.:

AF XY:

0.000612

AC XY:

445

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

AC:

AN:

33478

Gnomad4 AMR exome

AF:

0.000112

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.0000252

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.00352

AC:

304

AN:

86258

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53378

Gnomad4 NFE exome

AF:

0.000350

AC:

389

AN:

1112006

Gnomad4 Remaining exome

AF:

0.000563

AC:

AN:

60392

Heterozygous variant carriers

114

172

229

286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

100

<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:

0.000309

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.000144

AC:

0.000144439

AN:

0.000144439

Gnomad4 AMR

AF:

0.0000654

AC:

0.0000654365

AN:

0.0000654365

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00228

AC:

0.00228311

AN:

0.00228311

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000412

AC:

0.000411728

AN:

0.000411728

Gnomad4 OTH

AF:

0.000473

AC:

0.000473485

AN:

0.000473485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<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:

0.000403

Hom.:

Bravo

AF:

0.000272

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000791

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cryptorchidism

Pathogenic:1Uncertain:1

Sep 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

INSL3: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0033

LIST_S2

Benign

0.40

M_CAP

Benign

0.039

MetaRNN

Benign

0.40

MetaSVM

Benign

-0.56

PrimateAI

Benign

0.25

PROVEAN

Benign

0.18

REVEL

Benign

0.21

Sift

Benign

0.35

Sift4G

Benign

0.42

Vest4

0.68

MVP

0.030

MPC

0.25

ClinPred

0.039

GERP RS

-3.1

Varity_R

0.047

gMVP

0.0061

Mutation Taster

=90/10

disease causing (ClinVar)

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