NM_005543.4:c.380C>G

Variant names:

• chr19-17816870-G-C
• NM_005543.4:c.380C>G

Variant summary

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

The NM_005543.4(INSL3):​c.380C>G​(p.Thr127Ser) 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T127I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: INSL3 NM_005543.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.209
• 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=0.29892707).

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.380C>G	p.Thr127Ser	missense	Exon 2 of 2	NP_005534.2
	INSL3	NM_001265587.2		c.*1C>G		3_prime_UTR	Exon 3 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.380C>G	p.Thr127Ser	missense	Exon 2 of 2	ENSP00000321724.6	P51460-1
	INSL3	ENST00000379695.5	TSL:1	c.*1C>G		3_prime_UTR	Exon 3 of 3	ENSP00000369017.4	P51460-2
	INSL3	ENST00000598577.1	TSL:1	c.*186C>G		3_prime_UTR	Exon 2 of 2	ENSP00000469309.1	M0QXQ3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.21
PROVEAN	Benign	0.35	N
REVEL	Benign	0.097
Sift	Benign	0.40	T
Sift4G	Benign	0.46	T
Polyphen		0.15	B
Vest4		0.019
MutPred		0.34		Gain of disorder (P = 0.0573)
MVP		0.87
ClinPred		0.080	T
GERP RS		2.8
Varity_R		0.062
Mutation Taster		=89/11	polymorphism

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

hg19: chr19-17927679;