19-17816591-C-T

Variant names:

• chr19-17816591-C-T
• rs1003887
• NM_005543.4:c.*263G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005543.4(INSL3):​c.*263G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.659 in 548,378 control chromosomes in the GnomAD database, including 119,954 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35554 hom., cov: 32)
  • Exomes 𝑓: 0.65 (84400 hom.)
• Consequence: INSL3 NM_005543.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.233
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 19-17816591-C-T is Benign according to our data. Variant chr19-17816591-C-T is described in ClinVar as Benign. ClinVar VariationId is 1174416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSL3	NM_005543.4	c.*263G>A		3_prime_UTR_variant	Exon 2 of 2	ENST00000317306.8	NP_005534.2
INSL3	NM_001265587.2	c.*280G>A		3_prime_UTR_variant	Exon 3 of 3		NP_001252516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSL3	ENST00000317306.8	c.*263G>A		3_prime_UTR_variant	Exon 2 of 2	1	NM_005543.4	ENSP00000321724.6
INSL3	ENST00000379695.5	c.*280G>A		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000369017.4
INSL3	ENST00000598577.1	c.*465G>A		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000469309.1

Frequencies

GnomAD3 genomes AF: 0.682 AC: 103529 AN: 151894 Hom.: 35500 Cov.: 32

Gnomad AFR AF: 0.760

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.627

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.634

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.750

Gnomad MID AF: 0.634

Gnomad NFE AF: 0.650

Gnomad OTH AF: 0.651

GnomAD4 exome AF: 0.650 AC: 257581 AN: 396366 Hom.: 84400 Cov.: 2 AF XY: 0.646 AC XY: 134842 AN XY: 208590

African (AFR) AF: 0.749 AC: 8594 AN: 11468

American (AMR) AF: 0.627 AC: 10746 AN: 17144

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 7405 AN: 12270

East Asian (EAS) AF: 0.652 AC: 17365 AN: 26642

South Asian (SAS) AF: 0.615 AC: 27590 AN: 44826

European-Finnish (FIN) AF: 0.731 AC: 17553 AN: 24018

Middle Eastern (MID) AF: 0.668 AC: 1147 AN: 1718

European-Non Finnish (NFE) AF: 0.647 AC: 152248 AN: 235402

Other (OTH) AF: 0.653 AC: 14933 AN: 22878

GnomAD4 genome AF: 0.682 AC: 103630 AN: 152012 Hom.: 35554 Cov.: 32 AF XY: 0.684 AC XY: 50816 AN XY: 74304

African (AFR) AF: 0.761 AC: 31561 AN: 41500

American (AMR) AF: 0.627 AC: 9556 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 2119 AN: 3472

East Asian (EAS) AF: 0.634 AC: 3279 AN: 5174

South Asian (SAS) AF: 0.629 AC: 3026 AN: 4810

European-Finnish (FIN) AF: 0.750 AC: 7915 AN: 10558

Middle Eastern (MID) AF: 0.640 AC: 187 AN: 292

European-Non Finnish (NFE) AF: 0.650 AC: 44145 AN: 67942

Other (OTH) AF: 0.647 AC: 1363 AN: 2108

Alfa AF: 0.659 Hom.: 65626

Bravo AF: 0.677

Asia WGS AF: 0.606 AC: 2107 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.9
DANN	Benign	0.45
PhyloP100		-0.23
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: rs1003887; hg19: chr19-17927400;