rs921986

Positions:

• chr17-18323767-C-T

Variant summary

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

The NM_144775.3(SMCR8):​c.*697C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 153,336 control chromosomes in the GnomAD database, including 13,309 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 0.39 (13232 hom., cov: 34)
  • Exomes 𝑓: 0.35 (77 hom.)
• Consequence: SMCR8 NM_144775.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.36

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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMCR8	NM_144775.3	c.*697C>T		3_prime_UTR_variant	2/2	ENST00000406438.5	NP_658988.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMCR8	ENST00000406438.5	c.*697C>T		3_prime_UTR_variant	2/2	1	NM_144775.3	ENSP00000385025	P1

Frequencies

GnomAD3 genomes AF: 0.388 AC: 59025 AN: 152112 Hom.: 13195 Cov.: 34

Gnomad AFR AF: 0.614

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.0777

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.365

GnomAD4 exome AF: 0.352 AC: 389 AN: 1106 Hom.: 77 Cov.: 0 AF XY: 0.339 AC XY: 200 AN XY: 590

Gnomad4 AFR exome AF: 0.583

Gnomad4 AMR exome AF: 0.357

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.358

Gnomad4 OTH exome AF: 0.375

GnomAD4 genome AF: 0.388 AC: 59121 AN: 152230 Hom.: 13232 Cov.: 34 AF XY: 0.381 AC XY: 28378 AN XY: 74430

Gnomad4 AFR AF: 0.614

Gnomad4 AMR AF: 0.290

Gnomad4 ASJ AF: 0.357

Gnomad4 EAS AF: 0.0783

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.325

Gnomad4 NFE AF: 0.323

Gnomad4 OTH AF: 0.366

Alfa AF: 0.321 Hom.: 16341

Bravo AF: 0.393

Asia WGS AF: 0.192 AC: 669 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.9
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs921986; hg19: chr17-18227081; COSMIC: COSV57398078; COSMIC: COSV57398078;