Genetic Variant NM_001033081.3:c.800C>T (chr1-39897667-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001033081.3(MYCL):c.800C>T(p.Ser267Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S267Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MYCL
NM_001033081.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.66

Variant links:

Genes affected

MYCL (HGNC:7555): (MYCL proto-oncogene, bHLH transcription factor) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within regulation of inner ear auditory receptor cell differentiation. Located in chromosome and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MYCL links:

MYCL-AS1 (HGNC:40386): (MYCL antisense RNA 1)

MYCL-AS1 links:

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ACMG classification

Classification made for transcript

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=0.16364548).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYCL	NM_001033081.3 link	c.800C>T	p.Ser267Phe	missense_variant	Exon 2 of 2	ENST00000372816.3	NP_001028253.1	P12524-1
MYCL	NM_001033082.3 link	c.890C>T	p.Ser297Phe	missense_variant	Exon 3 of 3		NP_001028254.2	P12524-3
MYCL-AS1	NR_183424.1 link	n.273-76G>A		intron_variant	Intron 1 of 2
MYCL-AS1	NR_183425.1 link	n.36-76G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYCL	ENST00000372816.3 link	c.800C>T	p.Ser267Phe	missense_variant	Exon 2 of 2	2	NM_001033081.3	ENSP00000361903.2	P12524-1
MYCL	ENST00000397332.3 link	c.890C>T	p.Ser297Phe	missense_variant	Exon 3 of 3	1		ENSP00000380494.2	P12524-3
MYCL-AS1	ENST00000418255.1 link	n.-78G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

.;D

Eigen

Benign

-0.10

Eigen_PC

Benign

0.016

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.5

.;M

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-3.3

D;D

REVEL

Benign

0.24

Sift

Benign

0.039

D;T

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.20

.;B

Vest4

0.088

MutPred

0.26

.;Loss of glycosylation at S267 (P = 0.0159);

MVP

0.50

MPC

1.1

ClinPred

0.87

GERP RS

3.9

Varity_R

0.13

gMVP

0.28

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over