19-17821381-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005543.4(INSL3):c.126A>G(p.Leu42=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 1,548,232 control chromosomes in the GnomAD database, including 104,071 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10499 hom., cov: 35)
  • Exomes 𝑓: 0.36 (93572 hom.)
• Consequence: INSL3 NM_005543.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0300

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 19-17821381-T-C is Benign according to our data. Variant chr19-17821381-T-C is described in ClinVar as [Benign]. Clinvar id is 1271020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-17821381-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSL3	NM_005543.4	c.126A>G	p.Leu42=	synonymous_variant	1/2	ENST00000317306.8
INSL3	NM_001265587.2	c.126A>G	p.Leu42=	synonymous_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSL3	ENST00000317306.8	c.126A>G	p.Leu42=	synonymous_variant	1/2	1	NM_005543.4	P1
INSL3	ENST00000379695.5	c.126A>G	p.Leu42=	synonymous_variant	1/3	1
INSL3	ENST00000598577.1	c.126A>G	p.Leu42=	synonymous_variant	1/2	1

Frequencies

GnomAD3 genomes AF: 0.362 AC: 55094 AN: 152070 Hom.: 10491 Cov.: 35

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.362

GnomAD3 exomes AF: 0.305 AC: 43412 AN: 142460 Hom.: 7645 AF XY: 0.299 AC XY: 22902 AN XY: 76700

Gnomad AFR exome AF: 0.383

Gnomad AMR exome AF: 0.288

Gnomad ASJ exome AF: 0.317

Gnomad EAS exome AF: 0.00867

Gnomad SAS exome AF: 0.177

Gnomad FIN exome AF: 0.428

Gnomad NFE exome AF: 0.380

Gnomad OTH exome AF: 0.339

GnomAD4 exome AF: 0.357 AC: 498736 AN: 1396044 Hom.: 93572 Cov.: 62 AF XY: 0.352 AC XY: 242607 AN XY: 688458

Gnomad4 AFR exome AF: 0.382

Gnomad4 AMR exome AF: 0.294

Gnomad4 ASJ exome AF: 0.319

Gnomad4 EAS exome AF: 0.00566

Gnomad4 SAS exome AF: 0.182

Gnomad4 FIN exome AF: 0.431

Gnomad4 NFE exome AF: 0.382

Gnomad4 OTH exome AF: 0.336

GnomAD4 genome AF: 0.362 AC: 55137 AN: 152188 Hom.: 10499 Cov.: 35 AF XY: 0.358 AC XY: 26641 AN XY: 74398

Gnomad4 AFR AF: 0.393

Gnomad4 AMR AF: 0.317

Gnomad4 ASJ AF: 0.318

Gnomad4 EAS AF: 0.0110

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.422

Gnomad4 NFE AF: 0.387

Gnomad4 OTH AF: 0.358

Alfa AF: 0.380 Hom.: 3861

Bravo AF: 0.355

Asia WGS AF: 0.0970 AC: 339 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cryptorchidism Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	6.3
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1047233; hg19: chr19-17932190; COSMIC: COSV57952905; COSMIC: COSV57952905;