chr18-74291795-C-T

Variant names:

• chr18-74291795-C-T
• rs1555691399
• NM_148923.4:c.81G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_148923.4(CYB5A):​c.81G>A​(p.Trp27*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYB5A NM_148923.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.01

Genes affected

CYB5A (HGNC:2570): (cytochrome b5 type A) The protein encoded by this gene is a membrane-bound cytochrome that reduces ferric hemoglobin (methemoglobin) to ferrous hemoglobin, which is required for stearyl-CoA-desaturase activity. Defects in this gene are a cause of type IV hereditary methemoglobinemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.8 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-74291795-C-T is Pathogenic according to our data. Variant chr18-74291795-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 524200.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5A	NM_148923.4	c.81G>A	p.Trp27*	stop_gained	Exon 1 of 5	ENST00000340533.9	NP_683725.1
CYB5A	NM_001190807.3	c.81G>A	p.Trp27*	stop_gained	Exon 1 of 4		NP_001177736.1
CYB5A	NM_001914.4	c.81G>A	p.Trp27*	stop_gained	Exon 1 of 6		NP_001905.1
CYB5A	XM_011525835.3	c.81G>A	p.Trp27*	stop_gained	Exon 1 of 4		XP_011524137.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5A	ENST00000340533.9	c.81G>A	p.Trp27*	stop_gained	Exon 1 of 5	1	NM_148923.4	ENSP00000341625.4
CYB5A	ENST00000494131.6	c.81G>A	p.Trp27*	stop_gained	Exon 1 of 6	1		ENSP00000436461.2
CYB5A	ENST00000397914.4	c.81G>A	p.Trp27*	stop_gained	Exon 1 of 4	3		ENSP00000381011.4
CYB5A	ENST00000583418.1	n.163G>A		non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Methemoglobinemia type 4 Pathogenic:2

May 17, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Likely Pathogenic, for Methemoglobinemia and ambiguous genitalia, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PVS1-Strong => PVS1 downgraded in strength to Strong. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.81
GERP RS		4.5

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555691399; hg19: chr18-71959030;