1-44784241-G-A

Variant names:

• chr1-44784241-G-A
• rs1274892461
• NM_153274.3:c.1391C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153274.3(BEST4):​c.1391C>T​(p.Ala464Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000384 in 1,301,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: BEST4 NM_153274.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.192

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08568275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BEST4	NM_153274.3	c.1391C>T	p.Ala464Val	missense_variant	Exon 9 of 9	ENST00000372207.4	NP_695006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BEST4	ENST00000372207.4	c.1391C>T	p.Ala464Val	missense_variant	Exon 9 of 9	1	NM_153274.3	ENSP00000361281.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000384 AC: 5 AN: 1301940 Hom.: 0 Cov.: 31 AF XY: 0.00000625 AC XY: 4 AN XY: 639762

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000479

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1391C>T (p.A464V) alteration is located in exon 9 (coding exon 9) of the BEST4 gene. This alteration results from a C to T substitution at nucleotide position 1391, causing the alanine (A) at amino acid position 464 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.6
DANN	Benign	0.94
DEOGEN2	Benign	0.031	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.086	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.22
Sift	Benign	0.38	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.052
MutPred		0.094		Loss of relative solvent accessibility (P = 0.0404);
MVP		0.50
MPC		0.84
ClinPred		0.068	T
GERP RS		0.069
Varity_R		0.023
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs1274892461; hg19: chr1-45249913;