1-54190829-G-C

Position:

• chr1-54190829-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001031672.4(CYB5RL):​c.266C>G​(p.Thr89Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000758 in 1,450,522 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: CYB5RL NM_001031672.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.00

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]

ENSG00000256407 (HGNC:):

MRPL37 (HGNC:14034): (mitochondrial ribosomal protein L37) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. [provided by RefSeq, Jul 2008]

ACMG classification

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=0.18781301).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYB5RL	NM_001031672.4	c.266C>G	p.Thr89Ser	missense_variant	4/8	ENST00000534324.6	NP_001026842.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYB5RL	ENST00000534324.6	c.266C>G	p.Thr89Ser	missense_variant	4/8	5	NM_001031672.4	ENSP00000434343.1
ENSG00000256407	ENST00000637610.1	n.198+4590C>G		intron_variant		5		ENSP00000490901.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000758 AC: 11 AN: 1450522 Hom.: 0 Cov.: 30 AF XY: 0.00000694 AC XY: 5 AN XY: 720338

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000994

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

The c.266C>G (p.T89S) alteration is located in exon 4 (coding exon 2) of the CYB5RL gene. This alteration results from a C to G substitution at nucleotide position 266, causing the threonine (T) at amino acid position 89 to be replaced by a serine (S). 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	0.11
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Benign	0.64
DEOGEN2	Benign	0.037	.;T;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.53	T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.20	N;N;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.050	N;N;N;N
REVEL	Benign	0.29
Sift	Benign	0.74	T;T;T;T
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.23	.;B;.;.
Vest4		0.33
MutPred		0.42		Gain of phosphorylation at Y93 (P = 0.132);Gain of phosphorylation at Y93 (P = 0.132);.;Gain of phosphorylation at Y93 (P = 0.132);
MVP		0.35
ClinPred		0.47	T
GERP RS		5.0
Varity_R		0.11
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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

Other links and lift over

dbSNP: rs1413186021; hg19: chr1-54656502;