dbSNP rs6523: INSL3:p.Thr60Ser (chr19-17821329-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005543.4(INSL3):c.178A>T(p.Thr60Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T60A) has been classified as Benign.

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

INSL3
NM_005543.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.068038285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSL3	NM_005543.4 link	c.178A>T	p.Thr60Ser	missense_variant	Exon 1 of 2	ENST00000317306.8	NP_005534.2	P51460-1
INSL3	NM_001265587.2 link	c.178A>T	p.Thr60Ser	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>T	p.Thr60Ser	missense_variant	Exon 1 of 2	1	NM_005543.4	ENSP00000321724.6	P51460-1
INSL3	ENST00000379695.5 link	c.178A>T	p.Thr60Ser	missense_variant	Exon 1 of 3	1		ENSP00000369017.4	P51460-2
INSL3	ENST00000598577.1 link	c.175A>T	p.Thr59Ser	missense_variant	Exon 1 of 2	1		ENSP00000469309.1	M0QXQ3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1395406

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688410

African (AFR)

AF:

0.00

AC:

AN:

31556

American (AMR)

AF:

0.00

AC:

AN:

35724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25144

East Asian (EAS)

AF:

0.00

AC:

AN:

35720

South Asian (SAS)

AF:

0.00

AC:

AN:

79216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5324

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078702

Other (OTH)

AF:

0.00

AC:

AN:

57894

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.81

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.23

T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.068

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

-0.34

N;N

PhyloP100

-0.79

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.87

N;N

REVEL

Benign

0.12

Sift

Benign

0.34

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.019

B;.

Vest4

0.082

MutPred

0.36

Gain of glycosylation at T60 (P = 0.0096);Gain of glycosylation at T60 (P = 0.0096);

MVP

0.32

MPC

0.038

ClinPred

0.098

GERP RS

1.2

PromoterAI

-0.028

Neutral

(source)

Varity_R

0.050

gMVP

0.017

Mutation Taster

=97/3

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over