chr19-17817032-C-T

Position:

• chr19-17817032-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_005543.4(INSL3):​c.218G>A​(p.Arg73Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,461,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: INSL3 NM_005543.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.41

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07177594).
• BS2: High AC in GnomAdExome4 at 39 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSL3	NM_005543.4	c.218G>A	p.Arg73Gln	missense_variant	2/2	ENST00000317306.8	NP_005534.2
INSL3	NM_001265587.2	c.313G>A	p.Asp105Asn	missense_variant	3/3		NP_001252516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSL3	ENST00000317306.8	c.218G>A	p.Arg73Gln	missense_variant	2/2	1	NM_005543.4	ENSP00000321724	P1
INSL3	ENST00000379695.5	c.313G>A	p.Asp105Asn	missense_variant	3/3	1		ENSP00000369017
INSL3	ENST00000598577.1	c.*24G>A		3_prime_UTR_variant	2/2	1		ENSP00000469309

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461158 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 726878

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.218G>A (p.R73Q) alteration is located in exon 2 (coding exon 2) of the INSL3 gene. This alteration results from a G to A substitution at nucleotide position 218, causing the arginine (R) at amino acid position 73 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.4
DANN	Uncertain	1.0
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0087	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.014
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.073	T
Vest4		0.15
MutPred		0.46		Gain of MoRF binding (P = 0.0628);
MVP		0.072
MPC		0.041
ClinPred		0.23	T
GERP RS		0.94
gMVP		0.014

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: rs1228235146; hg19: chr19-17927841; COSMIC: COSV57953774; COSMIC: COSV57953774;