rs1555099968

Positions:

• chr11-61956897-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_004183.4(BEST1):​c.535A>G​(p.Asn179Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N179H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BEST1 NM_004183.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.12

Genes affected

BEST1 (HGNC:12703): (bestrophin 1) This gene encodes a member of the bestrophin gene family. This small gene family is characterized by proteins with a highly conserved N-terminus with four to six transmembrane domains. Bestrophins may form chloride ion channels or may regulate voltage-gated L-type calcium-ion channels. Bestrophins are generally believed to form calcium-activated chloride-ion channels in epithelial cells but they have also been shown to be highly permeable to bicarbonate ion transport in retinal tissue. Mutations in this gene are responsible for juvenile-onset vitelliform macular dystrophy (VMD2), also known as Best macular dystrophy, in addition to adult-onset vitelliform macular dystrophy (AVMD) and other retinopathies. Alternative splicing results in multiple variants encoding distinct isoforms.[provided by RefSeq, Nov 2008]

LOC107984334 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity BEST1_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_004183.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-61956897-A-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• PP5: Variant 11-61956897-A-G is Pathogenic according to our data. Variant chr11-61956897-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438484.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-61956897-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BEST1	NM_004183.4	c.535A>G	p.Asn179Asp	missense_variant	5/11	ENST00000378043.9
LOC107984334	XR_001748245.2	n.1797T>C		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BEST1	ENST00000378043.9	c.535A>G	p.Asn179Asp	missense_variant	5/11	1	NM_004183.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vitelliform macular dystrophy 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

MAGI'S LAB - Medical Genetics Laboratory, MAGI GROUP

Sep 11, 2017

Assessment via ACMG Guidelines: PM1 Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation PM2 Absent from controls (or at extremely low frequency if recessive) (table 6) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium PP2 Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology Likely pathogenic 2 Moderate (PM1-PM6) AND >=2 supporting (PP1-PP5) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Pathogenic	0.87
Sift	Benign	0.050	D;T;D
Sift4G	Benign	0.26	T;T;T
Polyphen		1.0	D;D;P
Vest4		0.84
MutPred		0.58		Loss of MoRF binding (P = 0.0659);.;.;
MVP		0.99
MPC		1.1
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.71
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555099968; hg19: chr11-61724369;