rs33999879

Variant names:

• chr3-160413559-A-G
• rs33999879
• NM_001002800.3:c.1067A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 14 publications found

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:56756): (TRIM59-IFT80 readthrough (NMD candidate)) This locus represents naturally occurring readthrough transcription between the neighboring TRIM59 (tripartite motif containing 59) and IFT80 (intraflagellar transport 80) genes on chromosome 3. The readthrough transcript is unlikely to produce a protein product. [provided by RefSeq, Jun 2017]

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001002800.3. 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
	SMC4	NM_001002800.3	MANE Select	c.1067A>G	p.Asn356Ser	missense	Exon 8 of 24	NP_001002800.1	Q9NTJ3-1
	SMC4	NM_005496.3		c.1067A>G	p.Asn356Ser	missense	Exon 7 of 23	NP_005487.3	Q9NTJ3-1
	SMC4	NM_001288753.2		c.992A>G	p.Asn331Ser	missense	Exon 8 of 24	NP_001275682.1	E9PD53

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC4	ENST00000357388.8	TSL:1 MANE Select	c.1067A>G	p.Asn356Ser	missense	Exon 8 of 24	ENSP00000349961.3	Q9NTJ3-1
	SMC4	ENST00000344722.5	TSL:1	c.1067A>G	p.Asn356Ser	missense	Exon 7 of 23	ENSP00000341382.5	Q9NTJ3-1
	SMC4	ENST00000489573.5	TSL:1	c.1067A>G	p.Asn356Ser	missense	Exon 8 of 9	ENSP00000420121.1	C9JR83

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

GnomAD2 exomes AF: 0.0524 AC: 11350 AN: 216542 AF XY: 0.0541

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 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

African (AFR) AF: 0.0220 AC: 649 AN: 29474

American (AMR) AF: 0.0240 AC: 781 AN: 32532

Ashkenazi Jewish (ASJ) AF: 0.0477 AC: 1157 AN: 24250

East Asian (EAS) AF: 0.0319 AC: 1237 AN: 38740

South Asian (SAS) AF: 0.0457 AC: 3563 AN: 77962

European-Finnish (FIN) AF: 0.123 AC: 6488 AN: 52852

Middle Eastern (MID) AF: 0.0763 AC: 417 AN: 5462

European-Non Finnish (NFE) AF: 0.0449 AC: 46641 AN: 1038556

Other (OTH) AF: 0.0479 AC: 2702 AN: 56438

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

African (AFR) AF: 0.0215 AC: 891 AN: 41538

American (AMR) AF: 0.0295 AC: 452 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0505 AC: 175 AN: 3466

East Asian (EAS) AF: 0.0439 AC: 228 AN: 5190

South Asian (SAS) AF: 0.0425 AC: 205 AN: 4828

European-Finnish (FIN) AF: 0.136 AC: 1429 AN: 10536

Middle Eastern (MID) AF: 0.0788 AC: 23 AN: 292

European-Non Finnish (NFE) AF: 0.0493 AC: 3353 AN: 68012

Other (OTH) AF: 0.0380 AC: 80 AN: 2108

Alfa AF: 0.0456 Hom.: 481

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 v4.9

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
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.063
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.097
Sift	Benign	0.76	T
Sift4G	Benign	0.77	T
Polyphen		0.0	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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs33999879; hg19: chr3-160131347;