19-17821377-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005543.4(INSL3):​c.130C>A​(p.Arg44Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 35)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INSL3 NM_005543.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41808233).

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>A	p.Arg44Ser	missense	Exon 1 of 2	NP_005534.2
	INSL3	NM_001265587.2		c.130C>A	p.Arg44Ser	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>A	p.Arg44Ser	missense	Exon 1 of 2	ENSP00000321724.6	P51460-1
	INSL3	ENST00000379695.5	TSL:1	c.130C>A	p.Arg44Ser	missense	Exon 1 of 3	ENSP00000369017.4	P51460-2
	INSL3	ENST00000598577.1	TSL:1	c.127C>A	p.Arg43Ser	missense	Exon 1 of 2	ENSP00000469309.1	M0QXQ3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.00 AC: 0 AN: 142308 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1396124 Hom.: 0 Cov.: 64 AF XY: 0.00 AC XY: 0 AN XY: 688490

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: 0.00 AC: 0 AN: 1078114

Other (OTH) AF: 0.00 AC: 0 AN: 57910

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	0.082
Eigen_PC	Benign	-0.027
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.47
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.22
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.056	T
Polyphen		0.96	D
Vest4		0.43
MutPred		0.76		Loss of MoRF binding (P = 0.015)
MVP		0.60
MPC		0.30
ClinPred		0.90	D
GERP RS		3.4
PromoterAI		-0.073	Neutral
Varity_R		0.50
gMVP		0.21
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;