19-17821348-G-C

Variant names:

• chr19-17821348-G-C
• rs113403604
• NM_005543.4:c.159C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_005543.4(INSL3):​c.159C>G​(p.Thr53Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,549,024 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: INSL3 NM_005543.4 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.918
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-17821348-G-C is Benign according to our data. Variant chr19-17821348-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3049387.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.918 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00121 (185/152346) while in subpopulation AFR AF = 0.00421 (175/41586). AF 95% confidence interval is 0.0037. There are 0 homozygotes in GnomAd4. There are 86 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 185 AD gene.

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.159C>G	p.Thr53Thr	synonymous	Exon 1 of 2	NP_005534.2
	INSL3	NM_001265587.2		c.159C>G	p.Thr53Thr	synonymous	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.159C>G	p.Thr53Thr	synonymous	Exon 1 of 2	ENSP00000321724.6	P51460-1
	INSL3	ENST00000379695.5	TSL:1	c.159C>G	p.Thr53Thr	synonymous	Exon 1 of 3	ENSP00000369017.4	P51460-2
	INSL3	ENST00000598577.1	TSL:1	c.156C>G	p.Thr52Thr	synonymous	Exon 1 of 2	ENSP00000469309.1	M0QXQ3

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 182 AN: 152228 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00415

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000518 AC: 74 AN: 142928 AF XY: 0.000428

Gnomad AFR exome AF: 0.00418

Gnomad AMR exome AF: 0.000163

Gnomad ASJ exome AF: 0.00232

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.000190 AC: 266 AN: 1396678 Hom.: 1 Cov.: 65 AF XY: 0.000184 AC XY: 127 AN XY: 688984

African (AFR) AF: 0.00453 AC: 143 AN: 31560

American (AMR) AF: 0.000168 AC: 6 AN: 35728

Ashkenazi Jewish (ASJ) AF: 0.00211 AC: 53 AN: 25144

East Asian (EAS) AF: 0.00 AC: 0 AN: 35730

South Asian (SAS) AF: 0.00 AC: 0 AN: 79214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47120

Middle Eastern (MID) AF: 0.00577 AC: 32 AN: 5546

European-Non Finnish (NFE) AF: 0.00000649 AC: 7 AN: 1078712

Other (OTH) AF: 0.000432 AC: 25 AN: 57924

GnomAD4 genome AF: 0.00121 AC: 185 AN: 152346 Hom.: 0 Cov.: 34 AF XY: 0.00115 AC XY: 86 AN XY: 74506

African (AFR) AF: 0.00421 AC: 175 AN: 41586

American (AMR) AF: 0.000261 AC: 4 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000790 Hom.: 1

Bravo AF: 0.00134

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	INSL3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.29
DANN	Benign	0.68
PhyloP100		-0.92
PromoterAI		0.059	Neutral
Mutation Taster		=100/0	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

dbSNP: rs113403604; hg19: chr19-17932157;