4-70249205-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 16/22 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17120543).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394997.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSN3	NM_001394997.1	MANE Select	c.295C>A	p.Leu99Met	missense	Exon 4 of 5	NP_001381926.1	P07498
	CSN3	NM_005212.3		c.295C>A	p.Leu99Met	missense	Exon 5 of 6	NP_005203.2	P07498

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSN3	ENST00000304954.4	TSL:1 MANE Select	c.295C>A	p.Leu99Met	missense	Exon 4 of 5	ENSP00000304822.3	P07498
	CSN3	ENST00000689459.1		c.295C>A	p.Leu99Met	missense	Exon 4 of 5	ENSP00000508633.1	P07498

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-2.0
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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

hg19: chr4-71114922;