11-61955173-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_004183.4(BEST1):c.219C>G(p.Ile73Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in Lovd as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I73L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BEST1 NM_004183.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.434

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain 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 chr11-61955172-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 812229.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 11-61955173-C-G is Pathogenic according to our data. Variant chr11-61955173-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BEST1	NM_004183.4	c.219C>G	p.Ile73Met	missense_variant	3/11	ENST00000378043.9
LOC107984334	XR_001748245.2	n.3521G>C		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BEST1	ENST00000378043.9	c.219C>G	p.Ile73Met	missense_variant	3/11	1	NM_004183.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 65

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;.
Eigen	Benign	0.0061
Eigen_PC	Benign	-0.025
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.53	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.79	N;N
REVEL	Uncertain	0.56
Sift	Benign	0.032	D;T
Sift4G	Uncertain	0.027	D;T
Polyphen		1.0	D;D
Vest4		0.44
MutPred		0.51		Loss of catalytic residue at I73 (P = 0.1519);.;
MVP		0.97
MPC		0.64
ClinPred		0.86	D
GERP RS		3.9
Varity_R		0.22
gMVP		0.67

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: rs1109748; hg19: chr11-61722645;