1-44784314-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_153274.3(BEST4):​c.1318C>G​(p.Pro440Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,396,944 control chromosomes in the GnomAD database, including 2 homozygotes. 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: 𝑓 0.00081 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: BEST4 NM_153274.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067542195).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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>G	p.Pro440Ala	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>G	p.Pro440Ala	missense	Exon 9 of 9	ENSP00000361281.3	Q8NFU0
	BEST4	ENST00000881840.1		c.1318C>G	p.Pro440Ala	missense	Exon 11 of 12	ENSP00000551899.1
	BEST4	ENST00000881841.1		c.1318C>G	p.Pro440Ala	missense	Exon 9 of 10	ENSP00000551900.1

Frequencies

GnomAD3 genomes AF: 0.000808 AC: 123 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000306 AC: 3 AN: 9810 AF XY: 0.000180

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: 0.000823

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00164 AC: 2045 AN: 1244630 Hom.: 2 Cov.: 31 AF XY: 0.00154 AC XY: 929 AN XY: 605204

African (AFR) AF: 0.000166 AC: 4 AN: 24072

American (AMR) AF: 0.000480 AC: 6 AN: 12506

Ashkenazi Jewish (ASJ) AF: 0.000392 AC: 7 AN: 17876

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

South Asian (SAS) AF: 0.0000342 AC: 2 AN: 58430

European-Finnish (FIN) AF: 0.000503 AC: 15 AN: 29802

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

European-Non Finnish (NFE) AF: 0.00189 AC: 1922 AN: 1018540

Other (OTH) AF: 0.00173 AC: 89 AN: 51466

GnomAD4 genome AF: 0.000808 AC: 123 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74470

African (AFR) AF: 0.000168 AC: 7 AN: 41572

American (AMR) AF: 0.000261 AC: 4 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00150 AC: 102 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000371 Hom.: 0

Bravo AF: 0.000752

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ExAC AF: 0.000226 AC: 15

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0068	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.5	L
PhyloP100		1.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.24
Sift	Benign	0.25	T
Sift4G	Benign	0.77	T
Polyphen		0.15	B
Vest4		0.086
MVP		0.64
MPC		0.83
ClinPred		0.055	T
GERP RS		3.6
Varity_R		0.031
gMVP		0.36
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;