19-7184331-G-A

Variant names:

• chr19-7184331-G-A
• rs138528064
• NM_000208.4:c.959C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_000208.4(INSR):​c.959C>T​(p.Thr320Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,613,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: INSR NM_000208.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.58
• Publications: 7 publications found

Genes affected

INSR (HGNC:6091): (insulin receptor) This gene encodes a member of the receptor tyrosine kinase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form a heterotetrameric receptor. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, which regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein. Mutations in this gene underlie the inherited severe insulin resistance syndromes including type A insulin resistance syndrome, Donohue syndrome and Rabson-Mendenhall syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

INSR Gene-Disease associations (from GenCC):

• insulin-resistance syndrome type A

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• Donohue syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• hyperinsulinism due to INSR deficiency

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
• Rabson-Mendenhall syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP2: Missense variant in the INSR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 3.8314 (above the threshold of 3.09). Trascript score misZ: 5.4593 (above the threshold of 3.09). GenCC associations: The gene is linked to Rabson-Mendenhall syndrome, hyperinsulinism due to INSR deficiency, Donohue syndrome, insulin-resistance syndrome type A.
• BP4: Computational evidence support a benign effect (MetaRNN=0.013263226).
• BP6: Variant 19-7184331-G-A is Benign according to our data. Variant chr19-7184331-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211200.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000828 (126/152092) while in subpopulation AFR AF = 0.00268 (111/41494). AF 95% confidence interval is 0.00227. There are 0 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000208.4. 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
	INSR	NM_000208.4	MANE Select	c.959C>T	p.Thr320Met	missense	Exon 3 of 22	NP_000199.2
	INSR	NM_001079817.3		c.959C>T	p.Thr320Met	missense	Exon 3 of 21	NP_001073285.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.959C>T	p.Thr320Met	missense	Exon 3 of 22	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.959C>T	p.Thr320Met	missense	Exon 3 of 21	ENSP00000342838.4
	INSR	ENST00000598216.1	TSL:1	n.934C>T		non_coding_transcript_exon	Exon 3 of 10

Frequencies

GnomAD3 genomes AF: 0.000829 AC: 126 AN: 151974 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00

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: 0.000480

GnomAD2 exomes AF: 0.000203 AC: 51 AN: 251124 AF XY: 0.000177

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000794 AC: 116 AN: 1461648 Hom.: 0 Cov.: 32 AF XY: 0.0000605 AC XY: 44 AN XY: 727122

African (AFR) AF: 0.00230 AC: 77 AN: 33474

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000354 AC: 2 AN: 5656

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111942

Other (OTH) AF: 0.000248 AC: 15 AN: 60380

GnomAD4 genome AF: 0.000828 AC: 126 AN: 152092 Hom.: 0 Cov.: 30 AF XY: 0.000794 AC XY: 59 AN XY: 74330

African (AFR) AF: 0.00268 AC: 111 AN: 41494

American (AMR) AF: 0.000852 AC: 13 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67994

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000420 Hom.: 0

Bravo AF: 0.00111

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	INSR-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	0.088
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.5	L
PhyloP100		3.6
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.40
Sift	Benign	0.23	T
Sift4G	Benign	0.19	T
Polyphen		0.53	P
Vest4		0.12
MVP		0.97
MPC		1.8
ClinPred		0.027	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.097
gMVP		0.40
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs138528064; hg19: chr19-7184342; COSMIC: COSV57165530;