NM_004183.4:c.715-15_715-4dupTCCTCCTCCTCC

Variant names:

• chr11-61958127-A-ATCCTCCTCCTCC
• rs1805182
• NM_004183.4:c.715-15_715-4dupTCCTCCTCCTCC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_004183.4(BEST1):​c.715-15_715-4dupTCCTCCTCCTCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BEST1 NM_004183.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -3.82
• Publications: 0 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, G2P, Labcorp Genetics (formerly Invitae)
• BEST1-related dominant retinopathy

  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, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• autosomal recessive bestrophinopathy

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

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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

LOC107984334 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 11-61958127-A-ATCCTCCTCCTCC is Benign according to our data. Variant chr11-61958127-A-ATCCTCCTCCTCC is described in ClinVar as Likely_benign. ClinVar VariationId is 1148797.Status of the report is criteria_provided_single_submitter, 1 stars.

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.715-15_715-4dupTCCTCCTCCTCC		splice_region intron	N/A	NP_004174.1	O76090-1
	BEST1	NM_001440571.1		c.715-15_715-4dupTCCTCCTCCTCC		splice_region intron	N/A	NP_001427500.1
	BEST1	NM_001440572.1		c.715-15_715-4dupTCCTCCTCCTCC		splice_region intron	N/A	NP_001427501.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BEST1	ENST00000378043.9	TSL:1 MANE Select	c.715-19_715-18insTCCTCCTCCTCC		intron	N/A	ENSP00000367282.4	O76090-1
	BEST1	ENST00000449131.6	TSL:1	c.535-19_535-18insTCCTCCTCCTCC		intron	N/A	ENSP00000399709.2	O76090-3
	BEST1	ENST00000526988.1	TSL:2	c.397-19_397-18insTCCTCCTCCTCC		intron	N/A	ENSP00000433195.1	B7Z1N8

Frequencies

GnomAD3 genomes AF: 0.000324 AC: 49 AN: 151142 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000559

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000777

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.0000954

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.000484

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000156 AC: 217 AN: 1393228 Hom.: 0 Cov.: 82 AF XY: 0.000164 AC XY: 114 AN XY: 693680

African (AFR) AF: 0.000501 AC: 16 AN: 31924

American (AMR) AF: 0.000279 AC: 12 AN: 43002

Ashkenazi Jewish (ASJ) AF: 0.000121 AC: 3 AN: 24734

East Asian (EAS) AF: 0.000188 AC: 7 AN: 37266

South Asian (SAS) AF: 0.000182 AC: 15 AN: 82534

European-Finnish (FIN) AF: 0.0000592 AC: 3 AN: 50648

Middle Eastern (MID) AF: 0.000542 AC: 3 AN: 5534

European-Non Finnish (NFE) AF: 0.000138 AC: 146 AN: 1060064

Other (OTH) AF: 0.000209 AC: 12 AN: 57522

GnomAD4 genome AF: 0.000324 AC: 49 AN: 151256 Hom.: 0 Cov.: 0 AF XY: 0.000298 AC XY: 22 AN XY: 73896

African (AFR) AF: 0.000557 AC: 23 AN: 41268

American (AMR) AF: 0.000263 AC: 4 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.000779 AC: 4 AN: 5136

South Asian (SAS) AF: 0.000420 AC: 2 AN: 4764

European-Finnish (FIN) AF: 0.0000954 AC: 1 AN: 10480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000207 AC: 14 AN: 67674

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000739 Hom.: 4495

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	BEST1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-3.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1805182; hg19: chr11-61725599;