Genetic Variant SMCR8:c.-300T>C (chr17-18315490-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_144775.3(SMCR8):c.-300T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 333,798 control chromosomes in the GnomAD database, including 81,146 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 0.72 ( 40413 hom., cov: 34)

Exomes 𝑓: 0.66 ( 40733 hom. )

Consequence

SMCR8
NM_144775.3 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.581

Publications

11 publications found

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 was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCR8	NM_144775.3 link	c.-300T>C		5_prime_UTR_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.-300T>C		5_prime_UTR_variant	Exon 1 of 2	1	NM_144775.3	ENSP00000385025.3		Q8TEV9-1

Frequencies

GnomAD3 genomes

AF:

0.722

AC:

109828

AN:

152070

Hom.:

40362

Cov.:

show subpopulations

Gnomad AFR

AF:

0.858

Gnomad AMI

AF:

0.557

Gnomad AMR

AF:

0.693

Gnomad ASJ

AF:

0.705

Gnomad EAS

AF:

0.543

Gnomad SAS

AF:

0.565

Gnomad FIN

AF:

0.716

Gnomad MID

AF:

0.661

Gnomad NFE

AF:

0.675

Gnomad OTH

AF:

0.709

GnomAD4 exome

AF:

0.664

AC:

120503

AN:

181610

Hom.:

40733

Cov.:

AF XY:

0.660

AC XY:

61638

AN XY:

93426

show subpopulations

African (AFR)

AF:

0.854

AC:

5172

AN:

6054

American (AMR)

AF:

0.690

AC:

4723

AN:

6844

Ashkenazi Jewish (ASJ)

AF:

0.722

AC:

4320

AN:

5980

East Asian (EAS)

AF:

0.519

AC:

6409

AN:

12344

South Asian (SAS)

AF:

0.572

AC:

8759

AN:

15312

European-Finnish (FIN)

AF:

0.725

AC:

6812

AN:

9390

Middle Eastern (MID)

AF:

0.706

AC:

593

AN:

840

European-Non Finnish (NFE)

AF:

0.670

AC:

76050

AN:

113592

Other (OTH)

AF:

0.681

AC:

7665

AN:

11254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1929

3857

5786

7714

9643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

450

900

1350

1800

2250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.722

AC:

109945

AN:

152188

Hom.:

40413

Cov.:

AF XY:

0.719

AC XY:

53504

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.859

AC:

35671

AN:

41546

American (AMR)

AF:

0.693

AC:

10606

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.705

AC:

2447

AN:

3470

East Asian (EAS)

AF:

0.543

AC:

2799

AN:

5152

South Asian (SAS)

AF:

0.566

AC:

2732

AN:

4830

European-Finnish (FIN)

AF:

0.716

AC:

7586

AN:

10594

Middle Eastern (MID)

AF:

0.646

AC:

190

AN:

294

European-Non Finnish (NFE)

AF:

0.675

AC:

45912

AN:

67984

Other (OTH)

AF:

0.707

AC:

1495

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1602

3205

4807

6410

8012

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

836

1672

2508

3344

4180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.692

Hom.:

11689

Bravo

AF:

0.725

Asia WGS

AF:

0.544

AC:

1893

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

0.58

PromoterAI

0.0054

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over