1-39897939-C-A

Position:

• chr1-39897939-C-A

Variant summary

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

The NM_001033081.3(MYCL):​c.528G>T​(p.Glu176Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,684 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E176K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYCL NM_001033081.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

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

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=0.15193927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYCL	NM_001033081.3	c.528G>T	p.Glu176Asp	missense_variant	2/2	ENST00000372816.3
MYCL-AS1	NR_183424.1	n.469C>A		non_coding_transcript_exon_variant	2/3
MYCL	NM_001033082.3	c.618G>T	p.Glu206Asp	missense_variant	3/3
MYCL-AS1	NR_183425.1	n.232C>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYCL	ENST00000372816.3	c.528G>T	p.Glu176Asp	missense_variant	2/2	2	NM_001033081.3	P4
MYCL	ENST00000397332.3	c.618G>T	p.Glu206Asp	missense_variant	3/3	1		A1
MYCL-AS1	ENST00000418255.1	n.195C>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461684 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727118

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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

Mar 18, 2024

The c.618G>T (p.E206D) alteration is located in exon 3 (coding exon 3) of the MYCL gene. This alteration results from a G to T substitution at nucleotide position 618, causing the glutamic acid (E) at amino acid position 206 to be replaced by an aspartic acid (D). 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	0.23
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.060
Sift	Benign	0.091	T;T
Sift4G	Benign	0.070	T;T
Polyphen		0.0010	.;B
Vest4		0.065
MutPred		0.63		.;Loss of catalytic residue at E176 (P = 0.1049);
MVP		0.040
MPC		0.62
ClinPred		0.68	D
GERP RS		4.2
Varity_R		0.20
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

LitVar

Other links and lift over

dbSNP: rs1570182488; hg19: chr1-40363611;