rs1800007

Variant names:

• chr11-61951915-T-A
• rs1800007
• NM_004183.4:c.109T>A

Your query was ambiguous. Multiple possible variants found:

• chr11-61951915-T-A
• chr11-61951915-T-C
• chr11-61951915-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_004183.4(BEST1):​c.109T>A​(p.Leu37Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L37P) 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: -0.761
• Publications: 46 publications found

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]

BEST1 Gene-Disease associations (from GenCC):

• autosomal dominant vitreoretinochoroidopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• inherited retinal dystrophy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• vitelliform macular dystrophy 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• autosomal recessive bestrophinopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa 50

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• adult-onset foveomacular vitelliform dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• MRCS syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• nanophthalmia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004183.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 209 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 0.61695 (below the threshold of 3.09). Trascript score misZ: 0.88358 (below the threshold of 3.09). GenCC associations: The gene is linked to vitelliform macular dystrophy 2, MRCS syndrome, autosomal recessive bestrophinopathy, autosomal dominant vitreoretinochoroidopathy, retinitis pigmentosa, retinitis pigmentosa 50, inherited retinal dystrophy, adult-onset foveomacular vitelliform dystrophy, nanophthalmia.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004183.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BEST1	NM_004183.4	MANE Select	c.109T>A	p.Leu37Ile	missense	Exon 2 of 11	NP_004174.1
	BEST1	NM_001440571.1		c.109T>A	p.Leu37Ile	missense	Exon 2 of 10	NP_001427500.1
	BEST1	NM_001440572.1		c.109T>A	p.Leu37Ile	missense	Exon 2 of 9	NP_001427501.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BEST1	ENST00000378043.9	TSL:1 MANE Select	c.109T>A	p.Leu37Ile	missense	Exon 2 of 11	ENSP00000367282.4
	BEST1	ENST00000449131.6	TSL:1	c.-29+1488T>A		intron	N/A	ENSP00000399709.2
	BEST1	ENST00000524926.5	TSL:2	n.109T>A		non_coding_transcript_exon	Exon 2 of 11	ENSP00000432681.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 49

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 54994

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	6.7
DANN	Benign	0.89
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.19	T
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.0	L
PhyloP100		-0.76
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.42
Sift	Benign	0.27	T
Sift4G	Benign	0.41	T
Polyphen		0.031	B
Vest4		0.10
MutPred		0.63		Gain of MoRF binding (P = 0.399)
MVP		0.78
ClinPred		0.21	T
GERP RS		-1.9
Varity_R		0.14
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs1800007; hg19: chr11-61719387;