1-44785610-C-T

Variant names:

• chr1-44785610-C-T
• rs375067026
• NM_153274.3:c.703G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_153274.3(BEST4):​c.703G>A​(p.Val235Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000475 in 1,473,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. V235L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000093 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: BEST4 NM_153274.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.89
• Publications: 0 publications found

Genes affected

BEST4 (HGNC:17106): (bestrophin 4) This gene is a member of the bestrophin gene family of anion channels. Bestrophin genes share a similar gene structure with highly conserved exon-intron boundaries, but with distinct 3' ends. Bestrophins are transmembrane proteins that contain a homologous region rich in aromatic residues, including an invariant arg-phe-pro motif. Mutation in one of the family members (bestrophin 1) is associated with vitelliform macular dystrophy. The bestrophin 4 gene is predominantly expressed in the colon. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153274.3. 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
	BEST4	NM_153274.3	MANE Select	c.703G>A	p.Val235Ile	missense	Exon 5 of 9	NP_695006.1	Q8NFU0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BEST4	ENST00000372207.4	TSL:1 MANE Select	c.703G>A	p.Val235Ile	missense	Exon 5 of 9	ENSP00000361281.3	Q8NFU0
	BEST4	ENST00000881840.1		c.703G>A	p.Val235Ile	missense	Exon 7 of 12	ENSP00000551899.1
	BEST4	ENST00000881841.1		c.703G>A	p.Val235Ile	missense	Exon 5 of 10	ENSP00000551900.1

Frequencies

GnomAD3 genomes AF: 0.00000930 AC: 1 AN: 107534 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000207

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000439 AC: 6 AN: 1366180 Hom.: 0 Cov.: 32 AF XY: 0.00000446 AC XY: 3 AN XY: 673200

African (AFR) AF: 0.00 AC: 0 AN: 30414

American (AMR) AF: 0.00 AC: 0 AN: 33650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24396

East Asian (EAS) AF: 0.00 AC: 0 AN: 33654

South Asian (SAS) AF: 0.00 AC: 0 AN: 73782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5590

European-Non Finnish (NFE) AF: 0.00000472 AC: 5 AN: 1059814

Other (OTH) AF: 0.0000177 AC: 1 AN: 56406

GnomAD4 genome AF: 0.00000930 AC: 1 AN: 107534 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 53416

African (AFR) AF: 0.00 AC: 0 AN: 28190

American (AMR) AF: 0.00 AC: 0 AN: 10794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2444

East Asian (EAS) AF: 0.00 AC: 0 AN: 3644

South Asian (SAS) AF: 0.00 AC: 0 AN: 3448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 176

European-Non Finnish (NFE) AF: 0.0000207 AC: 1 AN: 48208

Other (OTH) AF: 0.00 AC: 0 AN: 1430

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.98	N
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.77		Loss of sheet (P = 0.1158)
MVP		0.85
MPC		1.8
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.70
gMVP		0.58
Mutation Taster		=72/28	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: rs375067026; hg19: chr1-45251282; COSMIC: COSV100944006; COSMIC: COSV100944006;