2-170199326-G-T

Variant names:

• chr2-170199326-G-T
• rs374020923
• NM_138995.5:c.121G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_138995.5(MYO3B):​c.121G>T​(p.Val41Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V41I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYO3B NM_138995.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.83
• Publications: 0 publications found

Genes affected

MYO3B (HGNC:15576): (myosin IIIB) This gene encodes one of the class III myosins. Myosins are ATPases, activated by actin, that move along actin filaments in the cell. This class of myosins are characterized by an amino-terminal kinase domain and shown to be present in photoreceptors. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

ENSG00000308085 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO3B	NM_138995.5	c.121G>T	p.Val41Phe	missense_variant	Exon 2 of 35	ENST00000408978.9	NP_620482.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO3B	ENST00000408978.9	c.121G>T	p.Val41Phe	missense_variant	Exon 2 of 35	1	NM_138995.5	ENSP00000386213.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461164 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726862

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111608

Other (OTH) AF: 0.00 AC: 0 AN: 60364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	.;T;T
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.9	H;H;.
PhyloP100		9.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	.;.;D
Polyphen		1.0	D;D;.
Vest4		0.94
MutPred		0.71		Loss of MoRF binding (P = 0.0901);Loss of MoRF binding (P = 0.0901);.;
MVP		0.97
MPC		0.50
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		-0.011	Neutral
Varity_R		0.99
gMVP		0.89
Mutation Taster		=19/81	disease causing

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

Other links and lift over

dbSNP: rs374020923; hg19: chr2-171055836;