1-44784314-G-A

Variant names:

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

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>T​(p.Pro440Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000803 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: 8.0e-7 (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=0.1412358).

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>T	p.Pro440Ser	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>T	p.Pro440Ser	missense	Exon 9 of 9	ENSP00000361281.3	Q8NFU0
	BEST4	ENST00000881840.1		c.1318C>T	p.Pro440Ser	missense	Exon 11 of 12	ENSP00000551899.1
	BEST4	ENST00000881841.1		c.1318C>T	p.Pro440Ser	missense	Exon 9 of 10	ENSP00000551900.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.03e-7 AC: 1 AN: 1244632 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 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: 0.0000358 AC: 1 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: 0.00 AC: 0 AN: 1018542

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Uncertain	0.97
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	-0.074	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.27
Sift	Benign	0.10	T
Sift4G	Benign	0.93	T
Polyphen		0.011	B
Vest4		0.070
MutPred		0.26		Loss of catalytic residue at P439 (P = 0.0116)
MVP		0.57
MPC		0.86
ClinPred		0.13	T
GERP RS		3.6
Varity_R		0.030
gMVP		0.43
Mutation Taster		=92/8	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;