rs2286663

Variant names:

• chr19-17821480-C-T
• rs2286663
• NM_005543.4:c.27G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-17821480-C-T
• chr19-17821480-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.74
• Publications: 8 publications found

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

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005543.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSL3	NM_005543.4	MANE Select	c.27G>A	p.Ala9Ala	synonymous	Exon 1 of 2	NP_005534.2
	INSL3	NM_001265587.2		c.27G>A	p.Ala9Ala	synonymous	Exon 1 of 3	NP_001252516.1	P51460-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSL3	ENST00000317306.8	TSL:1 MANE Select	c.27G>A	p.Ala9Ala	synonymous	Exon 1 of 2	ENSP00000321724.6	P51460-1
	INSL3	ENST00000379695.5	TSL:1	c.27G>A	p.Ala9Ala	synonymous	Exon 1 of 3	ENSP00000369017.4	P51460-2
	INSL3	ENST00000598577.1	TSL:1	c.24G>A	p.Ala8Ala	synonymous	Exon 1 of 2	ENSP00000469309.1	M0QXQ3

Frequencies

GnomAD3 genomes AF: 0.0750 AC: 11410 AN: 152196 Hom.: 562 Cov.: 32

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

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.: 34 AF XY: 0.0602 AC XY: 39939 AN XY: 663144

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

GnomAD4 genome AF: 0.0750 AC: 11428 AN: 152314 Hom.: 565 Cov.: 32 AF XY: 0.0786 AC XY: 5852 AN XY: 74472

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: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0482 AC: 3281 AN: 68024

Other (OTH) AF: 0.0667 AC: 141 AN: 2114

Alfa AF: 0.0562 Hom.: 64

Bravo AF: 0.0820

Asia WGS AF: 0.147 AC: 512 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.5
DANN	Benign	0.93
PhyloP100		-3.7
PromoterAI		-0.016	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2286663; hg19: chr19-17932289; COSMIC: COSV57953013; COSMIC: COSV57953013;