rs376282820

Variant names:

• chr20-3854664-C-T
• rs376282820
• ENST00000416600.6:c.-209C>T

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -1 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4_Moderate

The NM_020746.5(MAVS):c.40C>T (p.Arg14Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000266 (AC=43) in the gnomAD database across 1,613,766 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.000333. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R14H: Likely_benign (ClinVar VariationId 2218084, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000025 (1 hom.)
• Consequence: MAVS NM_020746.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.34
• Publications: 3 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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000333 — borderline rare for unknown gene (threshold 0.001) — PM2 supporting.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_020746.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MAVS NM_020746.5	MANE Select	c.40C>T p.Arg14Cys	missense	Exon 2 of 7	Prot: NP_065797.2 UniProt:
	MAVS NM_001206491.2		c.-209C>T	5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	Prot: NP_001193420.1 UniProt:
	MAVS NM_001385663.1		c.-508C>T	5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	Prot: NP_001372592.1 UniProt:

MAVS NM_020746.5

MANE Select

HGVSc / HGVSpc.40C>Tp.Arg14Cys

Exon rankExon 2 of 7

missense

Prot: NP_065797.2UniProt: Q7Z434-1

MAVS NM_001206491.2

HGVSc / HGVSpc.-209C>T

Exon rankExon 2 of 6

5_prime_UTR_premature_start_codon_gain

Prot: NP_001193420.1UniProt: Q7Z434-4

MAVS NM_001385663.1

HGVSc / HGVSpc.-508C>T

Exon rankExon 2 of 8

5_prime_UTR_premature_start_codon_gain

Prot: NP_001372592.1UniProt: Q7Z434-4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MAVS ENST00000416600.6	TSL:1	c.-209C>T	5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	Prot: ENSP00000413749.2 UniProt:
	MAVS ENST00000428216.4	TSL:1MANE Select	c.40C>T p.Arg14Cys	missense	Exon 2 of 7	Prot: ENSP00000401980.2 UniProt:
	MAVS ENST00000416600.6	TSL:1	c.-209C>T	5_prime_UTR	Exon 2 of 6	Prot: ENSP00000413749.2 UniProt:

MAVS ENST00000416600.6

TSL:1

HGVSc / HGVSpc.-209C>T

Exon rankExon 2 of 6

5_prime_UTR_premature_start_codon_gain

Prot: ENSP00000413749.2UniProt: Q7Z434-4

MAVS ENST00000428216.4

TSL:1MANE Select

HGVSc / HGVSpc.40C>Tp.Arg14Cys

Exon rankExon 2 of 7

missense

Prot: ENSP00000401980.2UniProt: Q7Z434-1

MAVS ENST00000416600.6

TSL:1

HGVSc / HGVSpc.-209C>T

Exon rankExon 2 of 6

5_prime_UTR

Prot: ENSP00000413749.2UniProt: Q7Z434-4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000460	AC:7	Hom:0	AN:152024	Cov:31
GnomAD2 exomes	AF: 0.000103	AC:26	Hom:	AN:251448	Cov:
GnomAD4 exome	AF: 0.0000246	AC:36	Hom:1	AN:1461742	Cov:30
GnomAD4 genome	AF: 0.0000460	AC:7	Hom:0	AN:152024	Cov:31
TOPMed (Bravo)	AF: 0.0000227	AC:6	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:33972	Cov:
Local & regional cohorts 4 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.0000985	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13006	Cov:
Turkish Variome	AF: 0.000177	AC:1	Hom:0	AN:5176	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000223	AC:2	Hom:0	AN:8960	Cov:

Showing 10 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.00	0	41958	0.0000299	2	66842
SCHEMA(Schizophrenia)	0.0000355	4	112556	0.0000158	3	189656

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	8.7
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.031	N
FuncVEP CTI	Benign	0.11
GPN-Star LLR	N/A	-2.7
GPN-Star score	N/A	2.7
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-0.97	T
Mutation Taster	N/A	98/2	polymorphism
MutationAssessor	Benign	1.5	L
PhyloP100	Benign	-1.3
popEVE	Benign	-3.5
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-4.0	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.0
REVEL	Benign	0.078
Sift	Benign	0.075	T
Sift4G	Benign	0.18	T
Varity_R	N/A	0.18
VESM-3B	Benign	-9.1

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs376282820;

hg19: chr20-3835311;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar