NM_005543.4:c.27G>C

Variant names:

• chr19-17821480-C-G
• rs2286663
• NM_005543.4:c.27G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_005543.4(INSL3):​c.27G>C​(p.Ala9Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000738 in 1,355,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A9A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: INSL3 NM_005543.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.74
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP7: Synonymous conserved (PhyloP=-3.74 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSL3	NM_005543.4	c.27G>C	p.Ala9Ala	synonymous_variant	Exon 1 of 2	ENST00000317306.8	NP_005534.2
INSL3	NM_001265587.2	c.27G>C	p.Ala9Ala	synonymous_variant	Exon 1 of 3		NP_001252516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSL3	ENST00000317306.8	c.27G>C	p.Ala9Ala	synonymous_variant	Exon 1 of 2	1	NM_005543.4	ENSP00000321724.6
INSL3	ENST00000379695.5	c.27G>C	p.Ala9Ala	synonymous_variant	Exon 1 of 3	1		ENSP00000369017.4
INSL3	ENST00000598577.1	c.24G>C	p.Ala8Ala	synonymous_variant	Exon 1 of 2	1		ENSP00000469309.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.38e-7 AC: 1 AN: 1355298 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 663262

African (AFR) AF: 0.00 AC: 0 AN: 29518

American (AMR) AF: 0.00 AC: 0 AN: 30882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23102

East Asian (EAS) AF: 0.00 AC: 0 AN: 34982

South Asian (SAS) AF: 0.00 AC: 0 AN: 74696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5228

European-Non Finnish (NFE) AF: 9.47e-7 AC: 1 AN: 1055430

Other (OTH) AF: 0.00 AC: 0 AN: 55802

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.7
DANN	Benign	0.81
PhyloP100		-3.7
PromoterAI		0.054	Neutral

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

Other links and lift over

dbSNP: rs2286663; hg19: chr19-17932289;