rs33999879

Positions:

• chr3-160413559-A-G

Variant summary

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

The NM_001002800.3(SMC4):​c.1067A>G​(p.Asn356Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0468 in 1,508,448 control chromosomes in the GnomAD database, including 2,005 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.045 (216 hom., cov: 31)
  • Exomes 𝑓: 0.047 (1789 hom.)
• Consequence: SMC4 NM_001002800.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0630

Genes affected

SMC4 (HGNC:14013): (structural maintenance of chromosomes 4) This gene belongs to the 'structural maintenance of chromosomes' (SMC) gene family. Members of this gene family play a role in two changes in chromosome structure during mitotic segregation of chromosomes- chromosome condensation and sister chromatid cohesion. The protein encoded by this gene is likely a subunit of the 13S condensin complex, which is involved in chromosome condensation. A pseudogene related to this gene is located on chromosome 2. [provided by RefSeq, Jun 2016]

TRIM59-IFT80 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011974573).
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC4	NM_001002800.3	c.1067A>G	p.Asn356Ser	missense_variant	8/24	ENST00000357388.8
TRIM59-IFT80	NR_148401.1	n.1147+24673T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC4	ENST00000357388.8	c.1067A>G	p.Asn356Ser	missense_variant	8/24	1	NM_001002800.3	P1

Frequencies

GnomAD3 genomes AF: 0.0454 AC: 6898 AN: 152064 Hom.: 216 Cov.: 31

Gnomad AFR AF: 0.0215

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0296

Gnomad ASJ AF: 0.0505

Gnomad EAS AF: 0.0438

Gnomad SAS AF: 0.0422

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0493

Gnomad OTH AF: 0.0388

GnomAD3 exomes AF: 0.0524 AC: 11350 AN: 216542 Hom.: 381 AF XY: 0.0541 AC XY: 6392 AN XY: 118234

Gnomad AFR exome AF: 0.0200

Gnomad AMR exome AF: 0.0227

Gnomad ASJ exome AF: 0.0460

Gnomad EAS exome AF: 0.0452

Gnomad SAS exome AF: 0.0456

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.0522

Gnomad OTH exome AF: 0.0508

GnomAD4 exome AF: 0.0469 AC: 63635 AN: 1356266 Hom.: 1789 Cov.: 24 AF XY: 0.0475 AC XY: 32206 AN XY: 678494

Gnomad4 AFR exome AF: 0.0220

Gnomad4 AMR exome AF: 0.0240

Gnomad4 ASJ exome AF: 0.0477

Gnomad4 EAS exome AF: 0.0319

Gnomad4 SAS exome AF: 0.0457

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.0449

Gnomad4 OTH exome AF: 0.0479

GnomAD4 genome AF: 0.0453 AC: 6895 AN: 152182 Hom.: 216 Cov.: 31 AF XY: 0.0485 AC XY: 3608 AN XY: 74396

Gnomad4 AFR AF: 0.0215

Gnomad4 AMR AF: 0.0295

Gnomad4 ASJ AF: 0.0505

Gnomad4 EAS AF: 0.0439

Gnomad4 SAS AF: 0.0425

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.0493

Gnomad4 OTH AF: 0.0380

Alfa AF: 0.0466 Hom.: 273

Bravo AF: 0.0379

TwinsUK AF: 0.0496 AC: 184

ALSPAC AF: 0.0485 AC: 187

ESP6500AA AF: 0.0191 AC: 83

ESP6500EA AF: 0.0494 AC: 423

ExAC AF: 0.0507 AC: 6138

Asia WGS AF: 0.0450 AC: 157 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.1
DANN	Benign	0.74
DEOGEN2	Benign	0.12	T;.;.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.73	.;T;T;T;T
MetaRNN	Benign	0.0012	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N;.;.;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.70	N;N;N;N;N
REVEL	Benign	0.097
Sift	Benign	0.76	T;T;T;T;T
Sift4G	Benign	0.77	T;T;T;T;T
Polyphen		0.0	B;B;.;B;B
Vest4		0.021
MPC		0.13
ClinPred		0.0012	T
GERP RS		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.038
gMVP		0.048

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs33999879; hg19: chr3-160131347;