Genetic Variant NM_144775.3: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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144775.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMCR8	NM_144775.3	MANE Select	c.-300T>C		5_prime_UTR	Exon 1 of 2	NP_658988.2	Q8TEV9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMCR8	ENST00000406438.5	TSL:1 MANE Select	c.-300T>C		5_prime_UTR	Exon 1 of 2	ENSP00000385025.3	Q8TEV9-1
	SMCR8	ENST00000926351.1		c.-300T>C		5_prime_UTR	Exon 1 of 2	ENSP00000596410.1

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 v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over