rs7957619

Variant names:

• chr12-109576074-G-A
• rs7957619
• NM_000431.4:c.155G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-109576074-G-A
• chr12-109576074-G-T

Variant summary

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

The NM_000431.4(MVK):​c.155G>A​(p.Ser52Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,614,064 control chromosomes in the GnomAD database, including 11,153 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S52I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1116 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10037 hom.)
• Consequence: MVK NM_000431.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 0.197
• Publications: 60 publications found

Genes affected

MVK (HGNC:7530): (mevalonate kinase) This gene encodes the peroxisomal enzyme mevalonate kinase. Mevalonate is a key intermediate, and mevalonate kinase a key early enzyme, in isoprenoid and sterol synthesis. Mevalonate kinase deficiency caused by mutation of this gene results in mevalonic aciduria, a disease characterized psychomotor retardation, failure to thrive, hepatosplenomegaly, anemia and recurrent febrile crises. Defects in this gene also cause hyperimmunoglobulinaemia D and periodic fever syndrome, a disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

MVK Gene-Disease associations (from GenCC):

• porokeratosis 3, disseminated superficial actinic type

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hyperimmunoglobulinemia D with periodic fever

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• mevalonate kinase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mevalonic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• disseminated superficial actinic porokeratosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• porokeratosis of Mibelli

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027855933).
• BP6: Variant 12-109576074-G-A is Benign according to our data. Variant chr12-109576074-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000431.4. 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
	MVK	NM_000431.4	MANE Select	c.155G>A	p.Ser52Asn	missense	Exon 3 of 11	NP_000422.1	Q03426
	MVK	NM_001414512.1		c.155G>A	p.Ser52Asn	missense	Exon 3 of 12	NP_001401441.1
	MVK	NM_001114185.3		c.155G>A	p.Ser52Asn	missense	Exon 3 of 11	NP_001107657.1	B2RDU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MVK	ENST00000228510.8	TSL:1 MANE Select	c.155G>A	p.Ser52Asn	missense	Exon 3 of 11	ENSP00000228510.3	Q03426
	MVK	ENST00000546277.6	TSL:5	c.155G>A	p.Ser52Asn	missense	Exon 3 of 11	ENSP00000438153.2	Q03426
	MVK	ENST00000878306.1		c.155G>A	p.Ser52Asn	missense	Exon 3 of 11	ENSP00000548365.1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16839 AN: 152090 Hom.: 1115 Cov.: 32

Gnomad AFR AF: 0.0891

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.0992

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.126

GnomAD2 exomes AF: 0.101 AC: 25336 AN: 251452 AF XY: 0.101

Gnomad AFR exome AF: 0.0908

Gnomad AMR exome AF: 0.0709

Gnomad ASJ exome AF: 0.189

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.111 AC: 161702 AN: 1461856 Hom.: 10037 Cov.: 32 AF XY: 0.110 AC XY: 80146 AN XY: 727228

African (AFR) AF: 0.0913 AC: 3057 AN: 33480

American (AMR) AF: 0.0763 AC: 3412 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4697 AN: 26136

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39700

South Asian (SAS) AF: 0.0424 AC: 3656 AN: 86254

European-Finnish (FIN) AF: 0.132 AC: 7060 AN: 53414

Middle Eastern (MID) AF: 0.127 AC: 733 AN: 5768

European-Non Finnish (NFE) AF: 0.119 AC: 132473 AN: 1111986

Other (OTH) AF: 0.109 AC: 6604 AN: 60396

GnomAD4 genome AF: 0.111 AC: 16852 AN: 152208 Hom.: 1116 Cov.: 32 AF XY: 0.109 AC XY: 8105 AN XY: 74404

African (AFR) AF: 0.0892 AC: 3706 AN: 41540

American (AMR) AF: 0.0990 AC: 1514 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 662 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.0359 AC: 173 AN: 4824

European-Finnish (FIN) AF: 0.137 AC: 1450 AN: 10594

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8857 AN: 67996

Other (OTH) AF: 0.125 AC: 264 AN: 2112

Alfa AF: 0.123 Hom.: 4456

Bravo AF: 0.106

TwinsUK AF: 0.109 AC: 403

ALSPAC AF: 0.108 AC: 418

ESP6500AA AF: 0.0890 AC: 392

ESP6500EA AF: 0.130 AC: 1119

ExAC AF: 0.102 AC: 12344

Asia WGS AF: 0.0220 AC: 79 AN: 3478

EpiCase AF: 0.137

EpiControl AF: 0.134

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (4)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Hyperimmunoglobulin D with periodic fever (1)
-	-	1	Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria (1)
-	-	1	Methylmalonic acidemia (1)
-	-	1	Mevalonic aciduria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.044
DANN	Benign	0.63
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.85	N
PhyloP100		0.20
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.025
MPC		0.33
ClinPred		0.00030	T
GERP RS		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.035
gMVP		0.31
Mutation Taster		=94/6	polymorphism (auto)

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

dbSNP: rs7957619; hg19: chr12-110013879; COSMIC: COSV57169590; COSMIC: COSV57169590;