chr11-61962762-T-C

Variant names:

• chr11-61962762-T-C
• rs1800009
• NM_004183.4:c.1608T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004183.4(BEST1):​c.1608T>C​(p.Thr536Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,613,872 control chromosomes in the GnomAD database, including 138,198 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15332 hom., cov: 32)
  • Exomes 𝑓: 0.39 (122866 hom.)
• Consequence: BEST1 NM_004183.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: -1.12
• Publications: 33 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]

FTH1 (HGNC:3976): (ferritin heavy chain 1) This gene encodes the heavy subunit of ferritin, the major intracellular iron storage protein in prokaryotes and eukaryotes. It is composed of 24 subunits of the heavy and light ferritin chains. Variation in ferritin subunit composition may affect the rates of iron uptake and release in different tissues. A major function of ferritin is the storage of iron in a soluble and nontoxic state. Defects in ferritin proteins are associated with several neurodegenerative diseases. This gene has multiple pseudogenes. Several alternatively spliced transcript variants have been observed, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

FTH1 Gene-Disease associations (from GenCC):

• hemochromatosis type 5

  Inheritance: AD, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• neurodegeneration with brain iron accumulation 9

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-61962762-T-C is Benign according to our data. Variant chr11-61962762-T-C is described in ClinVar as Benign. ClinVar VariationId is 99682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

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.1608T>C	p.Thr536Thr	synonymous	Exon 10 of 11	NP_004174.1	O76090-1
	BEST1	NM_001440571.1		c.1608T>C	p.Thr536Thr	synonymous	Exon 10 of 10	NP_001427500.1
	BEST1	NM_001440572.1		c.1527T>C	p.Thr509Thr	synonymous	Exon 9 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.1608T>C	p.Thr536Thr	synonymous	Exon 10 of 11	ENSP00000367282.4	O76090-1
	BEST1	ENST00000449131.6	TSL:1	c.1428T>C	p.Thr476Thr	synonymous	Exon 9 of 9	ENSP00000399709.2	O76090-3
	BEST1	ENST00000534553.5	TSL:2	c.*503T>C		3_prime_UTR	Exon 5 of 5	ENSP00000431189.1	E9PMB5

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65727 AN: 151896 Hom.: 15321 Cov.: 32

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.863

Gnomad SAS AF: 0.699

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.410

GnomAD2 exomes AF: 0.460 AC: 115612 AN: 251412 AF XY: 0.462

Gnomad AFR exome AF: 0.504

Gnomad AMR exome AF: 0.502

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.861

Gnomad FIN exome AF: 0.369

Gnomad NFE exome AF: 0.346

Gnomad OTH exome AF: 0.401

GnomAD4 exome AF: 0.391 AC: 570908 AN: 1461858 Hom.: 122866 Cov.: 74 AF XY: 0.398 AC XY: 289639 AN XY: 727220

African (AFR) AF: 0.493 AC: 16505 AN: 33480

American (AMR) AF: 0.490 AC: 21914 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 9586 AN: 26136

East Asian (EAS) AF: 0.904 AC: 35897 AN: 39696

South Asian (SAS) AF: 0.670 AC: 57812 AN: 86254

European-Finnish (FIN) AF: 0.365 AC: 19479 AN: 53418

Middle Eastern (MID) AF: 0.367 AC: 2118 AN: 5768

European-Non Finnish (NFE) AF: 0.344 AC: 382667 AN: 1111990

Other (OTH) AF: 0.413 AC: 24930 AN: 60396

GnomAD4 genome AF: 0.433 AC: 65788 AN: 152014 Hom.: 15332 Cov.: 32 AF XY: 0.444 AC XY: 32975 AN XY: 74308

African (AFR) AF: 0.500 AC: 20734 AN: 41430

American (AMR) AF: 0.444 AC: 6784 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 1268 AN: 3466

East Asian (EAS) AF: 0.864 AC: 4467 AN: 5168

South Asian (SAS) AF: 0.699 AC: 3367 AN: 4820

European-Finnish (FIN) AF: 0.372 AC: 3939 AN: 10578

Middle Eastern (MID) AF: 0.401 AC: 117 AN: 292

European-Non Finnish (NFE) AF: 0.351 AC: 23839 AN: 67966

Other (OTH) AF: 0.409 AC: 862 AN: 2108

Alfa AF: 0.400 Hom.: 10772

Bravo AF: 0.438

Asia WGS AF: 0.712 AC: 2478 AN: 3478

EpiCase AF: 0.352

EpiControl AF: 0.350

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (5)
-	-	1	Autosomal dominant vitreoretinochoroidopathy (1)
-	-	1	Iron Overload (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis Pigmentosa, Recessive (1)
-	-	1	Vitelliform macular dystrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.53
DANN	Benign	0.67
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs1800009; hg19: chr11-61730234; COSMIC: COSV108022925; COSMIC: COSV108022925;