1-54174654-C-A

Variant names:

• chr1-54174654-C-A
• rs762288981
• NM_001031672.4:c.913G>T

Variant summary

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

The NM_001031672.4(CYB5RL):​c.913G>T​(p.Ala305Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,460,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CYB5RL NM_001031672.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.683

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:):

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=0.1458297).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5RL	NM_001031672.4	c.913G>T	p.Ala305Ser	missense_variant	Exon 8 of 8	ENST00000534324.6	NP_001026842.2
CYB5RL	NM_001353353.2	c.676G>T	p.Ala226Ser	missense_variant	Exon 6 of 6		NP_001340282.1
CYB5RL	NM_001353354.2	c.469G>T	p.Ala157Ser	missense_variant	Exon 7 of 7		NP_001340283.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5RL	ENST00000534324.6	c.913G>T	p.Ala305Ser	missense_variant	Exon 8 of 8	5	NM_001031672.4	ENSP00000434343.1
ENSG00000256407	ENST00000637610.1	n.303+9507G>T		intron_variant	Intron 3 of 9	5		ENSP00000490901.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1460174 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 726174

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: 0.0000216

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 15, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.913G>T (p.A305S) alteration is located in exon 8 (coding exon 6) of the CYB5RL gene. This alteration results from a G to T substitution at nucleotide position 913, causing the alanine (A) at amino acid position 305 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	0.091
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0037	.;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Uncertain	-0.0031	T
MutationAssessor	Uncertain	2.0	.;M
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0080	D;T
Sift4G	Uncertain	0.018	D;D
Polyphen		0.72	.;P
Vest4		0.23
MutPred		0.50		.;Gain of glycosylation at A305 (P = 0.0401);
MVP		0.39
ClinPred		0.50	D
GERP RS		5.1
Varity_R		0.055
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs762288981; hg19: chr1-54640327;