4-70249239-G-T

Variant names:

• chr4-70249239-G-T
• rs1048152
• NM_001394997.1:c.329G>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001394997.1(CSN3):​c.329G>T​(p.Arg110Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,613,820 control chromosomes in the GnomAD database, including 10,482 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1116 hom., cov: 32)
  • Exomes 𝑓: 0.10 (9366 hom.)
• Consequence: CSN3 NM_001394997.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.27

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068630576).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSN3	NM_001394997.1	c.329G>T	p.Arg110Leu	missense_variant	Exon 4 of 5	ENST00000304954.4	NP_001381926.1
CSN3	NM_005212.3	c.329G>T	p.Arg110Leu	missense_variant	Exon 5 of 6		NP_005203.2
CSN3	XM_017007761.2	c.329G>T	p.Arg110Leu	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.329G>T	p.Arg110Leu	missense_variant	Exon 4 of 5	1	NM_001394997.1	ENSP00000304822.3
CSN3	ENST00000689459.1	c.329G>T	p.Arg110Leu	missense_variant	Exon 4 of 5			ENSP00000508633.1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16788 AN: 151914 Hom.: 1115 Cov.: 32

Gnomad AFR AF: 0.0894

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.0873

Gnomad OTH AF: 0.129

GnomAD3 exomes AF: 0.137 AC: 34452 AN: 250972 Hom.: 2889 AF XY: 0.132 AC XY: 17957 AN XY: 135634

Gnomad AFR exome AF: 0.0886

Gnomad AMR exome AF: 0.239

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.240

Gnomad SAS exome AF: 0.129

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.0938

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.104 AC: 152428 AN: 1461788 Hom.: 9366 Cov.: 33 AF XY: 0.105 AC XY: 76129 AN XY: 727178

Gnomad4 AFR exome AF: 0.0884

Gnomad4 AMR exome AF: 0.230

Gnomad4 ASJ exome AF: 0.166

Gnomad4 EAS exome AF: 0.245

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.146

Gnomad4 NFE exome AF: 0.0885

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.110 AC: 16792 AN: 152032 Hom.: 1116 Cov.: 32 AF XY: 0.117 AC XY: 8691 AN XY: 74282

Gnomad4 AFR AF: 0.0894

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.230

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.158

Gnomad4 NFE AF: 0.0873

Gnomad4 OTH AF: 0.127

Alfa AF: 0.0865 Hom.: 400

Bravo AF: 0.114

TwinsUK AF: 0.0866 AC: 321

ALSPAC AF: 0.0882 AC: 340

ESP6500AA AF: 0.0878 AC: 387

ESP6500EA AF: 0.0919 AC: 790

ExAC AF: 0.130 AC: 15725

Asia WGS AF: 0.184 AC: 642 AN: 3478

EpiCase AF: 0.0982

EpiControl AF: 0.0982

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.022
DANN	Benign	0.87
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	L
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.042
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.035	D
Polyphen		0.086	B
Vest4		0.076
MPC		0.062
ClinPred		0.0052	T
GERP RS		-5.3
Varity_R		0.074
gMVP		0.29

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: rs1048152; hg19: chr4-71114956; COSMIC: COSV59243739;