17-18317360-C-T

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

1
5
11

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]

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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
SMCR8NM_144775.3 linkc.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
SMCR8ENST00000406438.5 linkc.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.:
31
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.:
64
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.:
31
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
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
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-2.5
D
REVEL
Uncertain
0.31
Sift
Benign
0.21
T
Sift4G
Benign
0.17
T
Polyphen
1.0
D
Vest4
0.28
MPC
0.33
ClinPred
0.029
T
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.

Other links and lift over

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