rs121912556

chr19-17816945-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM5 BP4 BS1_Supporting BS2

The NM_005543.4(INSL3):c.305G>A(p.Arg102His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000491 in 1,614,046 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00051 (6 hom.)
• Consequence: INSL3 NM_005543.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 0.258

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 Likely_benign. Variant got -4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-17816946-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14831.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3963346).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00051 (745/1461834) while in subpopulation SAS AF= 0.00352 (304/86258). AF 95% confidence interval is 0.0032. There are 6 homozygotes in gnomad4_exome. There are 445 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSL3	NM_005543.4	c.305G>A	p.Arg102His	missense_variant	2/2	ENST00000317306.8
INSL3	NM_001265587.2	c.400G>A	p.Ala134Thr	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSL3	ENST00000317306.8	c.305G>A	p.Arg102His	missense_variant	2/2	1	NM_005543.4	P1
INSL3	ENST00000379695.5	c.400G>A	p.Ala134Thr	missense_variant	3/3	1
INSL3	ENST00000598577.1	c.*111G>A		3_prime_UTR_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152094 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000689 AC: 173 AN: 251090 Hom.: 2 AF XY: 0.000942 AC XY: 128 AN XY: 135822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000485

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000510 AC: 745 AN: 1461834 Hom.: 6 Cov.: 31 AF XY: 0.000612 AC XY: 445 AN XY: 727218

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00352

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000350

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152212 Hom.: 0 Cov.: 31 AF XY: 0.000349 AC XY: 26 AN XY: 74416

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000392 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000791 AC: 96

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cryptorchidism Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 20, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2003	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	15
Dann	Uncertain	0.99
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.56	T
MutationTaster	Benign	3.2e-11	A;A
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.21
Sift	Benign	0.35	T
Sift4G	Benign	0.42	T
Vest4		0.68
MVP		0.030
MPC		0.25
ClinPred		0.039	T
GERP RS		-3.1
gMVP		0.0061

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: rs121912556; hg19: chr19-17927754;