1-44786562-G-T

Variant names:

• chr1-44786562-G-T
• rs1322233557
• NM_153274.3:c.382C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_153274.3(BEST4):​c.382C>A​(p.Leu128Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,398,084 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L128V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: BEST4 NM_153274.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.70
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.382C>A	p.Leu128Ile	missense	Exon 3 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.382C>A	p.Leu128Ile	missense	Exon 3 of 9	ENSP00000361281.3	Q8NFU0
	BEST4	ENST00000881840.1		c.382C>A	p.Leu128Ile	missense	Exon 5 of 12	ENSP00000551899.1
	BEST4	ENST00000881841.1		c.382C>A	p.Leu128Ile	missense	Exon 3 of 10	ENSP00000551900.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398084 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 689700

African (AFR) AF: 0.00 AC: 0 AN: 31636

American (AMR) AF: 0.00 AC: 0 AN: 35750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25156

East Asian (EAS) AF: 0.00 AC: 0 AN: 35848

South Asian (SAS) AF: 0.00 AC: 0 AN: 79274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4918

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1079236

Other (OTH) AF: 0.00 AC: 0 AN: 57906

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	0.92	L
PhyloP100		4.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.59
Sift	Benign	0.53	T
Sift4G	Benign	0.60	T
Polyphen		0.95	P
Vest4		0.43
MutPred		0.54		Gain of catalytic residue at A132 (P = 0.2307)
MVP		0.79
MPC		1.7
ClinPred		0.86	D
GERP RS		5.1
Varity_R		0.35
gMVP		0.41
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1322233557; hg19: chr1-45252234;