rs121918287

Variant names:

• chr11-61959892-G-A
• rs121918287
• NM_004183.4:c.949G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-61959892-G-A
• chr11-61959892-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PP2 PP3 PP5

The NM_004183.4(BEST1):​c.949G>A​(p.Val317Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,522 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V317L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: BEST1 NM_004183.4 missense, splice_region
• Scores: Splicing: ADA: 0.9985
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.04
• Publications: 12 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: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• neurodegeneration with brain iron accumulation 9

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

LOC107984334 (HGNC:):

ACMG classification

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

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_004183.4
• 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.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 11-61959892-G-A is Pathogenic according to our data. Variant chr11-61959892-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2742.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BEST1	NM_004183.4	MANE Select	c.949G>A	p.Val317Met	missense splice_region	Exon 9 of 11	NP_004174.1
	BEST1	NM_001363593.3		c.-24G>A		5_prime_UTR_premature_start_codon_gain	Exon 7 of 8	NP_001350522.1
	BEST1	NM_001440571.1		c.949G>A	p.Val317Met	missense splice_region	Exon 9 of 10	NP_001427500.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BEST1	ENST00000378043.9	TSL:1 MANE Select	c.949G>A	p.Val317Met	missense splice_region	Exon 9 of 11	ENSP00000367282.4
	BEST1	ENST00000449131.6	TSL:1	c.769G>A	p.Val257Met	missense splice_region	Exon 8 of 9	ENSP00000399709.2
	FTH1	ENST00000530019.5	TSL:4	c.274C>T	p.Pro92Ser	missense	Exon 3 of 3	ENSP00000433470.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461522 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727004

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111876

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive bestrophinopathy Pathogenic:1

Jan 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0084	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.29	T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		8.0
PROVEAN	Benign	1.4	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0060	D
Vest4		0.71
MutPred		0.42		Gain of helix (P = 0.027)
MVP		0.94
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.71
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.020		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: rs121918287; hg19: chr11-61727364;