rs12939757

chr17-18327346-A-G

Variant summary

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

The NM_144775.3(SMCR8):c.*4276A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 152,252 control chromosomes in the GnomAD database, including 5,617 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (5614 hom., cov: 33)
  • Exomes 𝑓: 0.32 (3 hom.)
• Consequence: SMCR8 NM_144775.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.736

Genes affected

SMCR8 (HGNC:17921): (SMCR8-C9orf72 complex subunit) Enables protein kinase binding activity and protein kinase inhibitor activity. Contributes to guanyl-nucleotide exchange factor activity. Involved in negative regulation of macromolecule metabolic process; regulation of TOR signaling; and regulation of macroautophagy. Located in chromatin; cytoplasm; and nucleoplasm. Part of guanyl-nucleotide exchange factor complex. Colocalizes with Atg1/ULK1 kinase complex. [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 (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMCR8	NM_144775.3	c.*4276A>G		3_prime_UTR_variant	2/2	ENST00000406438.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMCR8	ENST00000406438.5	c.*4276A>G		3_prime_UTR_variant	2/2	1	NM_144775.3	P1

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39926 AN: 152062 Hom.: 5615 Cov.: 33

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.0735

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.256

GnomAD4 exome AF: 0.319 AC: 23 AN: 72 Hom.: 3 Cov.: 0 AF XY: 0.278 AC XY: 15 AN XY: 54

Gnomad4 AMR exome AF: 0.250

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.750

Gnomad4 NFE exome AF: 0.296

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.262 AC: 39936 AN: 152180 Hom.: 5614 Cov.: 33 AF XY: 0.259 AC XY: 19252 AN XY: 74416

Gnomad4 AFR AF: 0.206

Gnomad4 AMR AF: 0.227

Gnomad4 ASJ AF: 0.314

Gnomad4 EAS AF: 0.0741

Gnomad4 SAS AF: 0.182

Gnomad4 FIN AF: 0.323

Gnomad4 NFE AF: 0.312

Gnomad4 OTH AF: 0.254

Alfa AF: 0.294 Hom.: 6365

Bravo AF: 0.249

Asia WGS AF: 0.137 AC: 476 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.69
Dann	Benign	0.56

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: rs12939757; hg19: chr17-18230660; COSMIC: COSV57398101; COSMIC: COSV57398101;