chr1-39901824-G-A

Position:

• chr1-39901824-G-A

Variant summary

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

The ENST00000397332.3(MYCL):​c.65C>T​(p.Ala22Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000446 in 1,122,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: MYCL ENST00000397332.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0410

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]

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=0.25885475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYCL	NM_001033081.3	c.-390C>T		5_prime_UTR_variant	1/2	ENST00000372816.3
MYCL	NM_001033082.3	c.65C>T	p.Ala22Val	missense_variant	1/3
MYCL	NM_005376.5	c.65C>T	p.Ala22Val	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYCL	ENST00000397332.3	c.65C>T	p.Ala22Val	missense_variant	1/3	1		A1
MYCL	ENST00000372815.1	c.65C>T	p.Ala22Val	missense_variant	1/2	1
MYCL	ENST00000372816.3	c.-390C>T		5_prime_UTR_variant	1/2	2	NM_001033081.3	P4
MYCL	ENST00000450953.3	c.-10+317C>T		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000446 AC: 5 AN: 1122178 Hom.: 0 Cov.: 32 AF XY: 0.00000911 AC XY: 5 AN XY: 548752

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000620

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000201

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000322

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

May 12, 2024

The c.65C>T (p.A22V) alteration is located in exon 1 (coding exon 1) of the MYCL gene. This alteration results from a C to T substitution at nucleotide position 65, causing the alanine (A) at amino acid position 22 to be replaced by a valine (V). 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
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.37	T;T
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	0.78	D;D;N;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.41	N;N
REVEL	Benign	0.090
Sift	Benign	0.28	T;D
Sift4G	Benign	0.39	T;T
Vest4		0.16
MutPred		0.70		Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);
MVP		0.36
MPC		0.66
ClinPred		0.56	D
GERP RS		0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.095

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1159370367; hg19: chr1-40367496;