22-35607408-G-T

Position:

• chr22-35607408-G-T

Variant summary

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

The ENST00000397326.7(MB):​c.354C>A​(p.Ser118Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: MB ENST00000397326.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.875

Genes affected

MB (HGNC:6915): (myoglobin) This gene encodes a member of the globin superfamily and is predominantly expressed in skeletal and cardiac muscles. The encoded protein forms a monomeric globular haemoprotein that is primarily responsible for the storage and facilitated transfer of oxygen from the cell membrane to the mitochondria. This protein also plays a role in regulating physiological levels of nitric oxide. Multiple transcript variants encoding distinct isoforms exist for this gene. [provided by RefSeq, May 2020]

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=0.15158558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MB	NM_005368.3	c.354C>A	p.Ser118Arg	missense_variant	3/3	ENST00000397326.7	NP_005359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MB	ENST00000397326.7	c.354C>A	p.Ser118Arg	missense_variant	3/3	1	NM_005368.3	ENSP00000380489.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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

Nov 21, 2022

The c.354C>A (p.S118R) alteration is located in exon 4 (coding exon 3) of the MB gene. This alteration results from a C to A substitution at nucleotide position 354, causing the serine (S) at amino acid position 118 to be replaced by an arginine (R). 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	0.25
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.040	T;T;T;T;T;T;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.72	T;.;T;.;.;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	.;L;L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.89	N;N;N;N;N;N;N
REVEL	Benign	0.028
Sift	Uncertain	0.0040	D;D;D;D;D;D;D
Sift4G	Uncertain	0.029	D;T;T;T;T;T;D
Polyphen		0.14	.;B;B;B;B;.;.
Vest4		0.17
MutPred		0.40		.;Gain of solvent accessibility (P = 0.0155);Gain of solvent accessibility (P = 0.0155);Gain of solvent accessibility (P = 0.0155);Gain of solvent accessibility (P = 0.0155);Gain of solvent accessibility (P = 0.0155);.;
MVP		0.34
MPC		0.19
ClinPred		0.43	T
GERP RS		1.6
Varity_R		0.30
gMVP		0.34

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: rs1420726851; hg19: chr22-36003455;