NM_005543.4:c.130C>T

Variant names:

• chr19-17821377-G-A
• rs1037546548
• NM_005543.4:c.130C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_005543.4(INSL3):​c.130C>T​(p.Arg44Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000284 in 1,548,340 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R44H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: INSL3 NM_005543.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.473
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BS2: High AC in GnomAdExome4 at 41 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSL3	NM_005543.4	MANE Select	c.130C>T	p.Arg44Cys	missense	Exon 1 of 2	NP_005534.2
	INSL3	NM_001265587.2		c.130C>T	p.Arg44Cys	missense	Exon 1 of 3	NP_001252516.1	P51460-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSL3	ENST00000317306.8	TSL:1 MANE Select	c.130C>T	p.Arg44Cys	missense	Exon 1 of 2	ENSP00000321724.6	P51460-1
	INSL3	ENST00000379695.5	TSL:1	c.130C>T	p.Arg44Cys	missense	Exon 1 of 3	ENSP00000369017.4	P51460-2
	INSL3	ENST00000598577.1	TSL:1	c.127C>T	p.Arg43Cys	missense	Exon 1 of 2	ENSP00000469309.1	M0QXQ3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000141 AC: 2 AN: 142308 AF XY: 0.0000130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000196

Gnomad OTH exome AF: 0.000241

GnomAD4 exome AF: 0.0000294 AC: 41 AN: 1396122 Hom.: 0 Cov.: 64 AF XY: 0.0000261 AC XY: 18 AN XY: 688488

African (AFR) AF: 0.00 AC: 0 AN: 31538

American (AMR) AF: 0.00 AC: 0 AN: 35642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25106

East Asian (EAS) AF: 0.00 AC: 0 AN: 35704

South Asian (SAS) AF: 0.00 AC: 0 AN: 79138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.0000315 AC: 34 AN: 1078112

Other (OTH) AF: 0.000121 AC: 7 AN: 57910

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	0.0014	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.063
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.47
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.25
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.70		Loss of MoRF binding (P = 0.0017)
MVP		0.80
MPC		0.32
ClinPred		0.82	D
GERP RS		3.4
PromoterAI		-0.097	Neutral
Varity_R		0.33
gMVP		0.15
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1037546548; hg19: chr19-17932186; COSMIC: COSV108862554; COSMIC: COSV108862554;