chr19-17816939-T-G

Variant names:

• chr19-17816939-T-G
• rs1251956919
• NM_005543.4:c.311A>C

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.311A>C​(p.His104Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 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: 0.0000068 (0 hom.)
• Consequence: INSL3 NM_005543.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.340

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=0.120880425).
• BS2: High AC in GnomAdExome4 at 10 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 rank	MANE	Protein	UniProt
INSL3	NM_005543.4	c.311A>C	p.His104Pro	missense_variant	Exon 2 of 2	ENST00000317306.8	NP_005534.2
INSL3	NM_001265587.2	c.406A>C	p.Thr136Pro	missense_variant	Exon 3 of 3		NP_001252516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSL3	ENST00000317306.8	c.311A>C	p.His104Pro	missense_variant	Exon 2 of 2	1	NM_005543.4	ENSP00000321724.6
INSL3	ENST00000379695.5	c.406A>C	p.Thr136Pro	missense_variant	Exon 3 of 3	1		ENSP00000369017.4
INSL3	ENST00000598577	c.*117A>C		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000469309.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251196 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135852

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.311A>C (p.H104P) alteration is located in exon 2 (coding exon 2) of the INSL3 gene. This alteration results from a A to C substitution at nucleotide position 311, causing the histidine (H) at amino acid position 104 to be replaced by a proline (P). 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	0.092
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	12
DANN	Benign	0.70
DEOGEN2	Benign	0.32	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.080
Sift	Benign	0.033	D
Sift4G	Benign	0.13	T
Polyphen		0.20	B
Vest4		0.17
MutPred		0.32		Gain of glycosylation at H104 (P = 0.052);
MVP		0.53
ClinPred		0.042	T
GERP RS		1.1
Varity_R		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs1251956919; hg19: chr19-17927748;