1-44784314-G-T

Variant names:

• chr1-44784314-G-T
• rs748003416
• NM_153274.3:c.1318C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153274.3(BEST4):​c.1318C>A​(p.Pro440Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000161 in 1,244,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. P440A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: BEST4 NM_153274.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.66
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21522996).

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.1318C>A	p.Pro440Thr	missense	Exon 9 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.1318C>A	p.Pro440Thr	missense	Exon 9 of 9	ENSP00000361281.3	Q8NFU0
	BEST4	ENST00000881840.1		c.1318C>A	p.Pro440Thr	missense	Exon 11 of 12	ENSP00000551899.1
	BEST4	ENST00000881841.1		c.1318C>A	p.Pro440Thr	missense	Exon 9 of 10	ENSP00000551900.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 9810 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000161 AC: 2 AN: 1244632 Hom.: 0 Cov.: 31 AF XY: 0.00000330 AC XY: 2 AN XY: 605206

African (AFR) AF: 0.00 AC: 0 AN: 24072

American (AMR) AF: 0.00 AC: 0 AN: 12506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17876

East Asian (EAS) AF: 0.00 AC: 0 AN: 27896

South Asian (SAS) AF: 0.00 AC: 0 AN: 58430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4042

European-Non Finnish (NFE) AF: 0.00000196 AC: 2 AN: 1018542

Other (OTH) AF: 0.00 AC: 0 AN: 51466

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.5	L
PhyloP100		1.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.28
Sift	Uncertain	0.017	D
Sift4G	Benign	0.49	T
Polyphen		0.29	B
Vest4		0.22
MutPred		0.30		Loss of catalytic residue at P439 (P = 0.0193)
MVP		0.67
MPC		1.1
ClinPred		0.25	T
GERP RS		3.6
Varity_R		0.057
gMVP		0.44
Mutation Taster		=90/10	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: rs748003416; hg19: chr1-45249986;