NM_144607.6:c.670G>C

Variant names:

• chr17-7859595-G-C
• rs776335221
• NM_144607.6:c.670G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_144607.6(CYB5D1):​c.670G>C​(p.Asp224His) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYB5D1 NM_144607.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.17

Genes affected

CYB5D1 (HGNC:26516): (cytochrome b5 domain containing 1) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

NAA38 (HGNC:28212): (N-alpha-acetyltransferase 38, NatC auxiliary subunit) Involved in negative regulation of apoptotic process. Located in cytoplasm and nucleoplasm. Part of NatC complex. Colocalizes with polysome. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000280046 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5D1	NM_144607.6	c.670G>C	p.Asp224His	missense_variant	Exon 4 of 4	ENST00000332439.5	NP_653208.2
CYB5D1	NM_001330110.2	c.*128G>C		3_prime_UTR_variant	Exon 4 of 4		NP_001317039.1
NAA38	NM_001330111.2	c.4-2397C>G		intron_variant	Intron 3 of 4		NP_001317040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5D1	ENST00000332439.5	c.670G>C	p.Asp224His	missense_variant	Exon 4 of 4	1	NM_144607.6	ENSP00000331479.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.670G>C (p.D224H) alteration is located in exon 4 (coding exon 4) of the CYB5D1 gene. This alteration results from a G to C substitution at nucleotide position 670, causing the aspartic acid (D) at amino acid position 224 to be replaced by a histidine (H). 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	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.3	D;.
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.89
MutPred		0.47		Loss of sheet (P = 0.0817);.;
MVP		0.71
MPC		1.8
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.92
gMVP		0.88

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: rs776335221; hg19: chr17-7762913;