1-39901035-T-G

Position:

• chr1-39901035-T-G

Variant summary

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

The NM_001033081.3(MYCL):​c.400A>C​(p.Ser134Arg) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYCL NM_001033081.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

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=0.13361016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYCL	NM_001033081.3	c.400A>C	p.Ser134Arg	missense_variant	1/2	ENST00000372816.3
MYCL	NM_001033082.3	c.490A>C	p.Ser164Arg	missense_variant	2/3
MYCL	NM_005376.5	c.490A>C	p.Ser164Arg	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYCL	ENST00000372816.3	c.400A>C	p.Ser134Arg	missense_variant	1/2	2	NM_001033081.3	P4
MYCL	ENST00000397332.3	c.490A>C	p.Ser164Arg	missense_variant	2/3	1		A1
MYCL	ENST00000372815.1	c.490A>C	p.Ser164Arg	missense_variant	2/2	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Aug 10, 2021

The c.490A>C (p.S164R) alteration is located in exon 2 (coding exon 2) of the MYCL gene. This alteration results from a A to C substitution at nucleotide position 490, causing the serine (S) at amino acid position 164 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	0.23
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	.;T;.
Eigen	Benign	0.055
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.065
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.89	.;P;.
Vest4		0.27
MutPred		0.31		.;Gain of solvent accessibility (P = 0.005);.;
MVP		0.095
MPC		1.1
ClinPred		0.33	T
GERP RS		3.9
Varity_R		0.17
gMVP		0.23

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: rs1644532374; hg19: chr1-40366707;