1-200911850-C-T

Variant names:

• chr1-200911850-C-T
• rs296520
• NM_001142569.3:c.1357C>T

Variant summary

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

The NM_001142569.3(INAVA):​c.1357C>T​(p.Arg453Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.739 in 1,564,990 control chromosomes in the GnomAD database, including 433,656 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40624 hom., cov: 31)
  • Exomes 𝑓: 0.74 (393032 hom.)
• Consequence: INAVA NM_001142569.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.650
• Publications: 28 publications found

Genes affected

INAVA (HGNC:25599): (innate immunity activator) Involved in several processes, including nucleotide-binding activity oligomerization domain containing 2 signaling pathway; positive regulation of cytokine production; and positive regulation of intracellular signal transduction. Located in cytoplasm and nucleus. Implicated in inflammatory bowel disease 29. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=7.791483E-7).
• BP6: Variant 1-200911850-C-T is Benign according to our data. Variant chr1-200911850-C-T is described in ClinVar as Benign. ClinVar VariationId is 767740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142569.3. 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
	INAVA	NM_001142569.3	MANE Select	c.1357C>T	p.Arg453Cys	missense	Exon 9 of 10	NP_001136041.1	Q3KP66-3
	INAVA	NM_018265.4		c.1612C>T	p.Arg538Cys	missense	Exon 9 of 10	NP_060735.4	Q3KP66-1
	INAVA	NM_001367289.1		c.1357C>T	p.Arg453Cys	missense	Exon 9 of 10	NP_001354218.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INAVA	ENST00000413687.3	TSL:2 MANE Select	c.1357C>T	p.Arg453Cys	missense	Exon 9 of 10	ENSP00000392105.2	Q3KP66-3
	INAVA	ENST00000367342.8	TSL:1	c.1654C>T	p.Arg552Cys	missense	Exon 9 of 10	ENSP00000356311.5	A0A8V8N8P9
	INAVA	ENST00000877560.1		c.1357C>T	p.Arg453Cys	missense	Exon 9 of 10	ENSP00000547619.1

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110159 AN: 151864 Hom.: 40592 Cov.: 31

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.814

Gnomad ASJ AF: 0.761

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.856

Gnomad FIN AF: 0.805

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.756

GnomAD2 exomes AF: 0.788 AC: 161920 AN: 205608 AF XY: 0.788

Gnomad AFR exome AF: 0.619

Gnomad AMR exome AF: 0.878

Gnomad ASJ exome AF: 0.782

Gnomad EAS exome AF: 0.997

Gnomad FIN exome AF: 0.796

Gnomad NFE exome AF: 0.719

Gnomad OTH exome AF: 0.786

GnomAD4 exome AF: 0.740 AC: 1045789 AN: 1413008 Hom.: 393032 Cov.: 55 AF XY: 0.744 AC XY: 522464 AN XY: 702434

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.627 AC: 20431 AN: 32568

American (AMR) AF: 0.872 AC: 37283 AN: 42752

Ashkenazi Jewish (ASJ) AF: 0.763 AC: 19158 AN: 25102

East Asian (EAS) AF: 0.986 AC: 38460 AN: 39014

South Asian (SAS) AF: 0.854 AC: 71707 AN: 83968

European-Finnish (FIN) AF: 0.792 AC: 35062 AN: 44252

Middle Eastern (MID) AF: 0.779 AC: 3242 AN: 4164

European-Non Finnish (NFE) AF: 0.717 AC: 776288 AN: 1082522

Other (OTH) AF: 0.753 AC: 44158 AN: 58666

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.725 AC: 110239 AN: 151982 Hom.: 40624 Cov.: 31 AF XY: 0.735 AC XY: 54603 AN XY: 74300

African (AFR) AF: 0.629 AC: 26073 AN: 41452

American (AMR) AF: 0.814 AC: 12439 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 2640 AN: 3470

East Asian (EAS) AF: 0.995 AC: 5132 AN: 5158

South Asian (SAS) AF: 0.856 AC: 4126 AN: 4820

European-Finnish (FIN) AF: 0.805 AC: 8521 AN: 10580

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.721 AC: 48995 AN: 67910

Other (OTH) AF: 0.759 AC: 1600 AN: 2108

Alfa AF: 0.710 Hom.: 4893

Bravo AF: 0.721

ESP6500AA AF: 0.629 AC: 2547

ESP6500EA AF: 0.703 AC: 5587

ExAC AF: 0.751 AC: 86818

ClinVar

ClinVar submissions as Germline

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	0.064
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.9
DANN	Benign	0.32
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	7.8e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.65
PROVEAN	Benign	1.1	N
REVEL	Benign	0.016
Sift	Benign	0.28	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.041
MPC		2.2
ClinPred		0.0080	T
GERP RS		0.76
Varity_R		0.056
gMVP		0.53
Mutation Taster		=100/0	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: rs296520; hg19: chr1-200880978; COSMIC: COSV66255792; COSMIC: COSV66255792;