4-70249205-C-A

Variant names:

• chr4-70249205-C-A
• NM_001394997.1:c.295C>A

Variant summary

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

The NM_001394997.1(CSN3):​c.295C>A​(p.Leu99Met) 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. 15/21 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: CSN3 NM_001394997.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.99

Genes affected

CSN3 (HGNC:2446): (casein kappa) Involved in lactation and protein stabilization. Located in extracellular space. [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=0.17120543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSN3	NM_001394997.1	c.295C>A	p.Leu99Met	missense_variant	Exon 4 of 5	ENST00000304954.4	NP_001381926.1
CSN3	NM_005212.3	c.295C>A	p.Leu99Met	missense_variant	Exon 5 of 6		NP_005203.2
CSN3	XM_017007761.2	c.295C>A	p.Leu99Met	missense_variant	Exon 4 of 5		XP_016863250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSN3	ENST00000304954.4	c.295C>A	p.Leu99Met	missense_variant	Exon 4 of 5	1	NM_001394997.1	ENSP00000304822.3
CSN3	ENST00000689459.1	c.295C>A	p.Leu99Met	missense_variant	Exon 4 of 5			ENSP00000508633.1

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

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.295C>A (p.L99M) alteration is located in exon 4 (coding exon 3) of the CSN3 gene. This alteration results from a C to A substitution at nucleotide position 295, causing the leucine (L) at amino acid position 99 to be replaced by a methionine (M). 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	0.18
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.1
DANN	Benign	0.97
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.075
Sift	Benign	0.14	T
Sift4G	Benign	0.24	T
Polyphen		0.76	P
Vest4		0.17
MutPred		0.68		Gain of phosphorylation at Y98 (P = 0.0876);
MVP		0.34
MPC		0.23
ClinPred		0.21	T
GERP RS		-3.3
Varity_R		0.064
gMVP		0.13

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.

Other links and lift over

hg19: chr4-71114922;