2-171553470-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024843.4(CYBRD1):c.527T>C(p.Met176Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000715 in 1,612,514 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M176I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00076 ( 1 hom. )

Consequence

CYBRD1
NM_024843.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.50

Variant links:

Genes affected

CYBRD1 (HGNC:20797): (cytochrome b reductase 1) This gene is a member of the cytochrome b(561) family that encodes an iron-regulated protein. It highly expressed in the duodenal brush border membrane. It has ferric reductase activity and is believed to play a physiological role in dietary iron absorption. [provided by RefSeq, Jul 2008]

CYBRD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.13865194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CYBRD1	NM_024843.4 linkuse as main transcript	c.527T>C	p.Met176Thr	missense_variant	3/4	ENST00000321348.9
CYBRD1	NM_001256909.2 linkuse as main transcript	c.353T>C	p.Met118Thr	missense_variant	3/4
CYBRD1	NM_001127383.2 linkuse as main transcript	c.318T>C	p.Tyr106=	synonymous_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYBRD1	ENST00000321348.9 linkuse as main transcript	c.527T>C	p.Met176Thr	missense_variant	3/4	1	NM_024843.4	P1	Q53TN4-1
CYBRD1	ENST00000375252.3 linkuse as main transcript	c.318T>C	p.Tyr106=	synonymous_variant	2/3	1			Q53TN4-2
CYBRD1	ENST00000409484.5 linkuse as main transcript	c.353T>C	p.Met118Thr	missense_variant	3/4	2			Q53TN4-3
CYBRD1	ENST00000445146.1 linkuse as main transcript	c.410T>C	p.Met137Thr	missense_variant	3/4	3

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000303

AC:

AN:

251110

Hom.:

AF XY:

0.000317

AC XY:

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000529

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000755

AC:

1103

AN:

1460308

Hom.:

Cov.:

AF XY:

0.000723

AC XY:

525

AN XY:

726410

show subpopulations

Gnomad4 AFR exome

AF:

0.000778

Gnomad4 AMR exome

AF:

0.000291

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:

0.000894

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.000329

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000557

Hom.:

Bravo

AF:

0.000378

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000222

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.527T>C (p.M176T) alteration is located in exon 3 (coding exon 3) of the CYBRD1 gene. This alteration results from a T to C substitution at nucleotide position 527, causing the methionine (M) at amino acid position 176 to be replaced by a threonine (T). 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

0.21

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.18

Cadd

Benign

Dann

Benign

0.83

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.72

T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.90

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.9

D;N;D

REVEL

Benign

0.15

Sift

Benign

0.36

T;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.13

.;B;.

Vest4

0.25

MVP

0.69

MPC

0.50

ClinPred

0.034

GERP RS

-0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over