17-18317360-C-T

Variant names:

• chr17-18317360-C-T
• rs8080966
• NM_144775.3:c.1571C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_144775.3(SMCR8):​c.1571C>T​(p.Pro524Leu) variant causes a missense change. The variant allele was found at a frequency of 0.29 in 1,613,768 control chromosomes in the GnomAD database, including 70,994 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 (5610 hom., cov: 31)
  • Exomes 𝑓: 0.29 (65384 hom.)
• Consequence: SMCR8 NM_144775.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.43
• Publications: 35 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016474426).
• 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 rank	MANE	Protein	UniProt
SMCR8	NM_144775.3	c.1571C>T	p.Pro524Leu	missense_variant	Exon 1 of 2	ENST00000406438.5	NP_658988.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCR8	ENST00000406438.5	c.1571C>T	p.Pro524Leu	missense_variant	Exon 1 of 2	1	NM_144775.3	ENSP00000385025.3

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39893 AN: 151892 Hom.: 5611 Cov.: 31

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.0745

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.256

GnomAD2 exomes AF: 0.258 AC: 64823 AN: 251308 AF XY: 0.258

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.324

Gnomad EAS exome AF: 0.0773

Gnomad FIN exome AF: 0.335

Gnomad NFE exome AF: 0.305

Gnomad OTH exome AF: 0.279

GnomAD4 exome AF: 0.293 AC: 428559 AN: 1461758 Hom.: 65384 Cov.: 64 AF XY: 0.289 AC XY: 210504 AN XY: 727178

African (AFR) AF: 0.203 AC: 6804 AN: 33480

American (AMR) AF: 0.222 AC: 9917 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 8202 AN: 26136

East Asian (EAS) AF: 0.0811 AC: 3221 AN: 39700

South Asian (SAS) AF: 0.180 AC: 15500 AN: 86256

European-Finnish (FIN) AF: 0.337 AC: 18000 AN: 53372

Middle Eastern (MID) AF: 0.223 AC: 1285 AN: 5764

European-Non Finnish (NFE) AF: 0.314 AC: 348868 AN: 1111930

Other (OTH) AF: 0.278 AC: 16762 AN: 60396

GnomAD4 genome AF: 0.263 AC: 39903 AN: 152010 Hom.: 5610 Cov.: 31 AF XY: 0.259 AC XY: 19236 AN XY: 74294

African (AFR) AF: 0.206 AC: 8548 AN: 41466

American (AMR) AF: 0.227 AC: 3466 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1087 AN: 3466

East Asian (EAS) AF: 0.0750 AC: 388 AN: 5172

South Asian (SAS) AF: 0.183 AC: 881 AN: 4820

European-Finnish (FIN) AF: 0.323 AC: 3407 AN: 10550

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.312 AC: 21233 AN: 67954

Other (OTH) AF: 0.254 AC: 534 AN: 2106

Alfa AF: 0.281 Hom.: 16311

Bravo AF: 0.249

TwinsUK AF: 0.311 AC: 1152

ALSPAC AF: 0.325 AC: 1252

ESP6500AA AF: 0.208 AC: 916

ESP6500EA AF: 0.302 AC: 2594

ExAC AF: 0.257 AC: 31220

Asia WGS AF: 0.137 AC: 477 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Benign	0.95
DEOGEN2	Benign	0.036	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.4
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.31
Sift	Benign	0.21	T
Sift4G	Benign	0.17	T
Vest4		0.28
ClinPred		0.029	T
GERP RS		5.9
Varity_R		0.11
gMVP		0.48
Mutation Taster		=87/13	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8080966; hg19: chr17-18220674; COSMIC: COSV58176095; COSMIC: COSV58176095;