Genetic Variant NM_001031672.4:c.749G>T (chr1-54174818-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001031672.4(CYB5RL):c.749G>T(p.Ser250Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: 6.8e-7 ( 0 hom. )

Consequence

CYB5RL
NM_001031672.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.956

Publications

0 publications found

Variant links:

Genes affected

CYB5RL (HGNC:32220): (cytochrome b5 reductase like) Predicted to enable cytochrome-b5 reductase activity, acting on NAD(P)H. Predicted to be involved in bicarbonate transport. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CYB5RL links:

ENSG00000256407 (HGNC:):

ENSG00000256407 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05831027).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031672.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYB5RL	NM_001031672.4	MANE Select	c.749G>T	p.Ser250Ile	missense	Exon 8 of 8	NP_001026842.2	Q6IPT4-1
CYB5RL	NM_001353353.2		c.512G>T	p.Ser171Ile	missense	Exon 6 of 6	NP_001340282.1
CYB5RL	NM_001353354.2		c.305G>T	p.Ser102Ile	missense	Exon 7 of 7	NP_001340283.1	Q6IPT4-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYB5RL	ENST00000534324.6	TSL:5 MANE Select	c.749G>T	p.Ser250Ile	missense	Exon 8 of 8	ENSP00000434343.1	Q6IPT4-1
CYB5RL	ENST00000420054.5	TSL:1	n.*743G>T		non_coding_transcript_exon	Exon 7 of 7	ENSP00000403021.1	F8WDU4
CYB5RL	ENST00000421415.5	TSL:1	n.*387G>T		non_coding_transcript_exon	Exon 7 of 7	ENSP00000394709.1	F8VW03

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460304

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726464

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111814

Other (OTH)

AF:

0.00

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

6.3

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.096

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.074

LIST_S2

Benign

0.56

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.058

MetaSVM

Benign

-0.31

MutationAssessor

Benign

0.97

PhyloP100

-0.96

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.85

REVEL

Benign

0.19

Sift

Benign

0.15

Sift4G

Benign

0.11

Polyphen

0.061

Vest4

0.19

MutPred

0.47

Loss of disorder (P = 0.0024)

MVP

0.24

ClinPred

0.10

GERP RS

-1.7

Varity_R

0.081

gMVP

0.32

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over