Genetic Variant INSL3:p.Ala9Ala (chr19-17821480-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005543.4(INSL3):c.27G>A(p.Ala9Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0619 in 1,507,378 control chromosomes in the GnomAD database, including 4,157 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.075 ( 565 hom., cov: 32)

Exomes 𝑓: 0.060 ( 3592 hom. )

Consequence

INSL3
NM_005543.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.74

Publications

8 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 19-17821480-C-T is Benign according to our data. Variant chr19-17821480-C-T is described in ClinVar as Benign. ClinVar VariationId is 1277901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.74 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSL3	NM_005543.4 link	c.27G>A	p.Ala9Ala	synonymous_variant	Exon 1 of 2	ENST00000317306.8	NP_005534.2	P51460-1
INSL3	NM_001265587.2 link	c.27G>A	p.Ala9Ala	synonymous_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.27G>A	p.Ala9Ala	synonymous_variant	Exon 1 of 2	1	NM_005543.4	ENSP00000321724.6	P51460-1
INSL3	ENST00000379695.5 link	c.27G>A	p.Ala9Ala	synonymous_variant	Exon 1 of 3	1		ENSP00000369017.4	P51460-2
INSL3	ENST00000598577.1 link	c.24G>A	p.Ala8Ala	synonymous_variant	Exon 1 of 2	1		ENSP00000469309.1	M0QXQ3

Frequencies

GnomAD3 genomes

AF:

0.0750

AC:

11410

AN:

152196

Hom.:

562

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0836

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.123

Gnomad ASJ

AF:

0.0628

Gnomad EAS

AF:

0.204

Gnomad SAS

AF:

0.0829

Gnomad FIN

AF:

0.0905

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0482

Gnomad OTH

AF:

0.0674

GnomAD2 exomes

AF:

0.102

AC:

11649

AN:

114038

AF XY:

0.0953

show subpopulations

Gnomad AFR exome

AF:

0.0998

Gnomad AMR exome

AF:

0.197

Gnomad ASJ exome

AF:

0.0649

Gnomad EAS exome

AF:

0.210

Gnomad FIN exome

AF:

0.0881

Gnomad NFE exome

AF:

0.0516

Gnomad OTH exome

AF:

0.0760

GnomAD4 exome

AF:

0.0604

AC:

81883

AN:

1355064

Hom.:

3592

Cov.:

AF XY:

0.0602

AC XY:

39939

AN XY:

663144

show subpopulations

African (AFR)

AF:

0.0897

AC:

2648

AN:

29514

American (AMR)

AF:

0.184

AC:

5675

AN:

30802

Ashkenazi Jewish (ASJ)

AF:

0.0621

AC:

1434

AN:

23086

East Asian (EAS)

AF:

0.234

AC:

8168

AN:

34960

South Asian (SAS)

AF:

0.0775

AC:

5785

AN:

74674

European-Finnish (FIN)

AF:

0.0811

AC:

3700

AN:

45648

Middle Eastern (MID)

AF:

0.0484

AC:

253

AN:

5224

European-Non Finnish (NFE)

AF:

0.0479

AC:

50545

AN:

1055366

Other (OTH)

AF:

0.0659

AC:

3675

AN:

55790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

4190

8380

12569

16759

20949

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2138

4276

6414

8552

10690

<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:

0.0750

AC:

11428

AN:

152314

Hom.:

565

Cov.:

AF XY:

0.0786

AC XY:

5852

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0835

AC:

3469

AN:

41562

American (AMR)

AF:

0.123

AC:

1885

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0628

AC:

218

AN:

3470

East Asian (EAS)

AF:

0.203

AC:

1054

AN:

5180

South Asian (SAS)

AF:

0.0832

AC:

402

AN:

4834

European-Finnish (FIN)

AF:

0.0905

AC:

961

AN:

10624

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0482

AC:

3281

AN:

68024

Other (OTH)

AF:

0.0667

AC:

141

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

546

1093

1639

2186

2732

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

264

396

528

660

<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:

0.0562

Hom.:

Bravo

AF:

0.0820

Asia WGS

AF:

0.147

AC:

512

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

3.5

(source)

DANN

Benign

0.93

PhyloP100

-3.7

PromoterAI

-0.016

Neutral

(source)

Mutation Taster

=100/0

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