chr19-17821381-T-C

Variant names:

• chr19-17821381-T-C
• rs1047233
• NM_005543.4:c.126A>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.126A>G​(p.Leu42Leu) 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:3
• Conservation: PhyloP100: 0.0300
• Publications: 17 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=-0.72).
• BP6: Variant 19-17821381-T-C is Benign according to our data. Variant chr19-17821381-T-C is described in ClinVar as Benign. ClinVar VariationId is 1271020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSL3	NM_005543.4	MANE Select	c.126A>G	p.Leu42Leu	synonymous	Exon 1 of 2	NP_005534.2
	INSL3	NM_001265587.2		c.126A>G	p.Leu42Leu	synonymous	Exon 1 of 3	NP_001252516.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSL3	ENST00000317306.8	TSL:1 MANE Select	c.126A>G	p.Leu42Leu	synonymous	Exon 1 of 2	ENSP00000321724.6
	INSL3	ENST00000379695.5	TSL:1	c.126A>G	p.Leu42Leu	synonymous	Exon 1 of 3	ENSP00000369017.4
	INSL3	ENST00000598577.1	TSL:1	c.123A>G	p.Leu41Leu	synonymous	Exon 1 of 2	ENSP00000469309.1

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

GnomAD2 exomes AF: 0.305 AC: 43412 AN: 142460 AF XY: 0.299

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 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

African (AFR) AF: 0.382 AC: 12037 AN: 31520

American (AMR) AF: 0.294 AC: 10470 AN: 35612

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 8003 AN: 25106

East Asian (EAS) AF: 0.00566 AC: 202 AN: 35702

South Asian (SAS) AF: 0.182 AC: 14380 AN: 79136

European-Finnish (FIN) AF: 0.431 AC: 20414 AN: 47400

Middle Eastern (MID) AF: 0.358 AC: 2012 AN: 5618

European-Non Finnish (NFE) AF: 0.382 AC: 411774 AN: 1078058

Other (OTH) AF: 0.336 AC: 19444 AN: 57892

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

African (AFR) AF: 0.393 AC: 16318 AN: 41554

American (AMR) AF: 0.317 AC: 4853 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1102 AN: 3470

East Asian (EAS) AF: 0.0110 AC: 57 AN: 5174

South Asian (SAS) AF: 0.170 AC: 822 AN: 4832

European-Finnish (FIN) AF: 0.422 AC: 4463 AN: 10580

Middle Eastern (MID) AF: 0.336 AC: 98 AN: 292

European-Non Finnish (NFE) AF: 0.387 AC: 26281 AN: 67962

Other (OTH) AF: 0.358 AC: 756 AN: 2112

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 09, 2021

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

Cryptorchidism Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.3
DANN	Benign	0.68
PhyloP100		0.030
PromoterAI		-0.028	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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