Genetic Variant SMCR8:p.Pro524Leu (chr17-18317360-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.26 ( 5610 hom., cov: 31)

Exomes 𝑓: 0.29 ( 65384 hom. )

Consequence

SMCR8
NM_144775.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.43

Variant links:

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]

SMCR8 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 link	c.1571C>T	p.Pro524Leu	missense_variant	Exon 1 of 2	ENST00000406438.5	NP_658988.2	Q8TEV9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCR8	ENST00000406438.5 link	c.1571C>T	p.Pro524Leu	missense_variant	Exon 1 of 2	1	NM_144775.3	ENSP00000385025.3		Q8TEV9-1

Frequencies

GnomAD3 genomes

AF:

0.263

AC:

39893

AN:

151892

Hom.:

5611

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.258

AC:

64823

AN:

251308

Hom.:

9119

AF XY:

0.258

AC XY:

34981

AN XY:

135844

show subpopulations

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 SAS exome

AF:

0.181

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.:

AF XY:

0.289

AC XY:

210504

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.203

Gnomad4 AMR exome

AF:

0.222

Gnomad4 ASJ exome

AF:

0.314

Gnomad4 EAS exome

AF:

0.0811

Gnomad4 SAS exome

AF:

0.180

Gnomad4 FIN exome

AF:

0.337

Gnomad4 NFE exome

AF:

0.314

Gnomad4 OTH exome

AF:

0.278

GnomAD4 genome

AF:

0.263

AC:

39903

AN:

152010

Hom.:

5610

Cov.:

AF XY:

0.259

AC XY:

19236

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.206

Gnomad4 AMR

AF:

0.227

Gnomad4 ASJ

AF:

0.314

Gnomad4 EAS

AF:

0.0750

Gnomad4 SAS

AF:

0.183

Gnomad4 FIN

AF:

0.323

Gnomad4 NFE

AF:

0.312

Gnomad4 OTH

AF:

0.254

Alfa

AF:

0.285

Hom.:

11784

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

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Benign

0.95

DEOGEN2

Benign

0.036

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.31

Sift

Benign

0.21

Sift4G

Benign

0.17

Polyphen

1.0

Vest4

0.28

MPC

0.33

ClinPred

0.029

GERP RS

5.9

Varity_R

0.11

gMVP

0.48

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over