chr19-17821329-T-C

Position:

• chr19-17821329-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005543.4(INSL3):​c.178A>G​(p.Thr60Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 1,547,416 control chromosomes in the GnomAD database, including 330,977 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.69 (37213 hom., cov: 35)
  • Exomes 𝑓: 0.65 (293764 hom.)
• Consequence: INSL3 NM_005543.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.785

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.494739E-6).
• BP6: Variant 19-17821329-T-C is Benign according to our data. Variant chr19-17821329-T-C is described in ClinVar as [Benign]. Clinvar id is 1253265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-17821329-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSL3	NM_005543.4	c.178A>G	p.Thr60Ala	missense_variant	1/2	ENST00000317306.8	NP_005534.2
INSL3	NM_001265587.2	c.178A>G	p.Thr60Ala	missense_variant	1/3		NP_001252516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSL3	ENST00000317306.8	c.178A>G	p.Thr60Ala	missense_variant	1/2	1	NM_005543.4	ENSP00000321724	P1
INSL3	ENST00000379695.5	c.178A>G	p.Thr60Ala	missense_variant	1/3	1		ENSP00000369017
INSL3	ENST00000598577.1	c.178A>G	p.Thr60Ala	missense_variant	1/2	1		ENSP00000469309

Frequencies

GnomAD3 genomes AF: 0.694 AC: 105597 AN: 152102 Hom.: 37162 Cov.: 35

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.627

Gnomad SAS AF: 0.631

Gnomad FIN AF: 0.728

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.645

Gnomad OTH AF: 0.654

GnomAD3 exomes AF: 0.649 AC: 91747 AN: 141390 Hom.: 29950 AF XY: 0.648 AC XY: 49431 AN XY: 76330

Gnomad AFR exome AF: 0.805

Gnomad AMR exome AF: 0.630

Gnomad ASJ exome AF: 0.606

Gnomad EAS exome AF: 0.632

Gnomad SAS exome AF: 0.624

Gnomad FIN exome AF: 0.724

Gnomad NFE exome AF: 0.640

Gnomad OTH exome AF: 0.643

GnomAD4 exome AF: 0.648 AC: 903435 AN: 1395196 Hom.: 293764 Cov.: 67 AF XY: 0.646 AC XY: 444951 AN XY: 688292

Gnomad4 AFR exome AF: 0.816

Gnomad4 AMR exome AF: 0.630

Gnomad4 ASJ exome AF: 0.603

Gnomad4 EAS exome AF: 0.661

Gnomad4 SAS exome AF: 0.627

Gnomad4 FIN exome AF: 0.720

Gnomad4 NFE exome AF: 0.642

Gnomad4 OTH exome AF: 0.647

GnomAD4 genome AF: 0.694 AC: 105696 AN: 152220 Hom.: 37213 Cov.: 35 AF XY: 0.696 AC XY: 51792 AN XY: 74418

Gnomad4 AFR AF: 0.815

Gnomad4 AMR AF: 0.634

Gnomad4 ASJ AF: 0.609

Gnomad4 EAS AF: 0.627

Gnomad4 SAS AF: 0.632

Gnomad4 FIN AF: 0.728

Gnomad4 NFE AF: 0.645

Gnomad4 OTH AF: 0.650

Alfa AF: 0.657 Hom.: 10622

Bravo AF: 0.693

TwinsUK AF: 0.654 AC: 2425

ALSPAC AF: 0.647 AC: 2492

ESP6500AA AF: 0.830 AC: 3090

ESP6500EA AF: 0.689 AC: 5029

ExAC AF: 0.505 AC: 30766

Asia WGS AF: 0.611 AC: 2125 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cryptorchidism Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.16
DANN	Benign	0.21
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.14	T;T
MetaRNN	Benign	0.0000015	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.2	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.89	N;N
REVEL	Benign	0.24
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.037
MPC		0.039
ClinPred		0.0090	T
GERP RS		1.2
Varity_R		0.048
gMVP		0.018

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

LitVar

Other links and lift over

dbSNP: rs6523; hg19: chr19-17932138; COSMIC: COSV57952843; COSMIC: COSV57952843;