20-3864757-C-T

Variant names:

• chr20-3864757-C-T
• NM_020746.5:c.1127C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020746.5(MAVS):​c.1127C>T​(p.Thr376Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAVS NM_020746.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44
• Publications: 0 publications found

Genes affected

MAVS (HGNC:29233): (mitochondrial antiviral signaling protein) This gene encodes an intermediary protein necessary in the virus-triggered beta interferon signaling pathways. It is required for activation of transcription factors which regulate expression of beta interferon and contributes to antiviral innate immunity. [provided by RefSeq, Jul 2020]

PANK2-AS1 (HGNC:40732): (PANK2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15475315).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020746.5. 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
	MAVS	NM_020746.5	MANE Select	c.1127C>T	p.Thr376Ile	missense	Exon 6 of 7	NP_065797.2	Q7Z434-1
	MAVS	NM_001206491.2		c.704C>T	p.Thr235Ile	missense	Exon 5 of 6	NP_001193420.1	Q7Z434-4
	MAVS	NM_001385663.1		c.704C>T	p.Thr235Ile	missense	Exon 7 of 8	NP_001372592.1	Q7Z434-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAVS	ENST00000428216.4	TSL:1 MANE Select	c.1127C>T	p.Thr376Ile	missense	Exon 6 of 7	ENSP00000401980.2	Q7Z434-1
	MAVS	ENST00000416600.6	TSL:1	c.704C>T	p.Thr235Ile	missense	Exon 5 of 6	ENSP00000413749.2	Q7Z434-4
	MAVS	ENST00000883971.1		c.1127C>T	p.Thr376Ile	missense	Exon 5 of 6	ENSP00000554030.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461768 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ 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 Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.4
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.066
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.061	T
Polyphen		0.56	P
Vest4		0.25
MutPred		0.36		Loss of glycosylation at T376 (P = 0.0236)
MVP		0.63
MPC		0.14
ClinPred		0.57	D
GERP RS		3.5
Varity_R		0.11
gMVP		0.15
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

hg19: chr20-3845404;