rs28940275

Variant names:

• chr11-61951822-A-C
• rs28940275
• NM_004183.4:c.16A>C
• BEST1 p.Thr6Pro

Your query was ambiguous. Multiple possible variants found:

• chr11-61951822-A-C
• chr11-61951822-A-G

Germline classificationCancer classification (beta)

Variant summary

Our verdict is

Likely pathogenic

+9 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_004183.4(BEST1):c.16A>C (p.Thr6Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.T6I: Likely_pathogenic (ClinVar VariationId 3249785, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BEST1 NM_004183.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:3 O:1
• Conservation: PhyloP100: 3.09
• Publications: 11 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• BEST1-related dominant retinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• vitelliform macular dystrophy 2

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

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

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• 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

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 16 pathogenic, 0 benign (OR vs. background: 165.0).
• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000286 by highest known P/LP ClinVar AF 0.000286) — PM2 moderate.
• PM5: Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.T6I: Likely_pathogenic (ClinVar VariationId 3249785, 1 star)
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
• PP5: ClinVar 0-star pathogenic — supporting (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BEST1	NM_004183.4	MANE Select	c.16A>C	p.Thr6Pro	missense	Exon 2 of 11	NP_004174.1	O76090-1
	BEST1	NM_001440571.1		c.16A>C	p.Thr6Pro	missense	Exon 2 of 10	NP_001427500.1
	BEST1	NM_001440572.1		c.16A>C	p.Thr6Pro	missense	Exon 2 of 9	NP_001427501.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BEST1	ENST00000378043.9	TSL:1 MANE Select	c.16A>C	p.Thr6Pro	missense	Exon 2 of 11	ENSP00000367282.4	O76090-1
	BEST1	ENST00000449131.6	TSL:1	c.-29+1395A>C		intron	N/A	ENSP00000399709.2	O76090-3
	BEST1	ENST00000534553.5	TSL:2	c.-212+1395A>C		intron	N/A	ENSP00000431189.1	E9PMB5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (3)
1	-	-	Vitelliform macular dystrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.1
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.010	D
Varity_R		0.85
Mutation Taster		=1/99	disease causing (ClinVar)

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

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

Other links and lift over

dbSNP: rs28940275;

hg19: chr11-61719294;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar