rs62638703

Variant names:

• chr9-5233855-C-A
• rs62638703
• NM_002195.2:c.398C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002195.2(INSL4):​c.398C>A​(p.Thr133Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,611,938 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (70 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (72 hom.)
• Consequence: INSL4 NM_002195.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.53
• Publications: 4 publications found

Genes affected

INSL4 (HGNC:6087): (insulin like 4) INSL4 encodes the insulin-like 4 protein, a member of the insulin superfamily. INSL4 encodes a precursor that undergoes post-translational cleavage to produce 3 polypeptide chains, A-C, that form tertiary structures composed of either all three chains, or just the A and B chains. Expression of INSL4 products occurs within the early placental cytotrophoblast and syncytiotrophoblast. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026692748).
• BP6: Variant 9-5233855-C-A is Benign according to our data. Variant chr9-5233855-C-A is described in ClinVar as Benign. ClinVar VariationId is 792121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0572 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002195.2. 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
	INSL4	NM_002195.2	MANE Select	c.398C>A	p.Thr133Asn	missense	Exon 2 of 2	NP_002186.1	Q14641

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSL4	ENST00000239316.4	TSL:1 MANE Select	c.398C>A	p.Thr133Asn	missense	Exon 2 of 2	ENSP00000239316.4	Q14641

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2670 AN: 152160 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.0590

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00446 AC: 1116 AN: 250104 AF XY: 0.00353

Gnomad AFR exome AF: 0.0607

Gnomad AMR exome AF: 0.00293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000709

Gnomad OTH exome AF: 0.00296

GnomAD4 exome AF: 0.00175 AC: 2557 AN: 1459660 Hom.: 72 Cov.: 29 AF XY: 0.00153 AC XY: 1114 AN XY: 726268

African (AFR) AF: 0.0615 AC: 2054 AN: 33404

American (AMR) AF: 0.00392 AC: 175 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39636

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5756

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1110220

Other (OTH) AF: 0.00436 AC: 263 AN: 60288

GnomAD4 genome AF: 0.0176 AC: 2683 AN: 152278 Hom.: 70 Cov.: 32 AF XY: 0.0175 AC XY: 1300 AN XY: 74460

African (AFR) AF: 0.0592 AC: 2459 AN: 41560

American (AMR) AF: 0.0114 AC: 174 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68018

Other (OTH) AF: 0.0156 AC: 33 AN: 2114

Alfa AF: 0.00719 Hom.: 95

Bravo AF: 0.0203

ESP6500AA AF: 0.0601 AC: 265

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00542 AC: 658

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.1
DANN	Benign	0.80
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.69	N
PhyloP100		-2.5
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.24
Sift	Benign	0.34	T
Sift4G	Benign	0.68	T
Polyphen		0.99	D
Vest4		0.075
MVP		0.58
MPC		0.0033
ClinPred		0.0082	T
GERP RS		-1.0
Varity_R		0.048
gMVP		0.087
Mutation Taster		=97/3	polymorphism (auto)

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: rs62638703; hg19: chr9-5233855;