Genetic Variant NM_144775.3:c.*4276A>G (chr17-18327346-A-G) – 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.*4276A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 152,252 control chromosomes in the GnomAD database, including 5,617 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

Frequency

Genomes: 𝑓 0.26 ( 5614 hom., cov: 33)

Exomes 𝑓: 0.32 ( 3 hom. )

Consequence

SMCR8
NM_144775.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.736

Publications

16 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=-0.86).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.309 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.*4276A>G		3_prime_UTR	Exon 2 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.*4276A>G		3_prime_UTR	Exon 2 of 2	ENSP00000385025.3	Q8TEV9-1
	SMCR8	ENST00000926351.1		c.*4276A>G		3_prime_UTR	Exon 2 of 2	ENSP00000596410.1

Frequencies

GnomAD3 genomes

AF:

0.263

AC:

39926

AN:

152062

Hom.:

5615

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:

0.0735

Gnomad SAS

AF:

0.181

Gnomad FIN

AF:

0.323

Gnomad MID

AF:

0.239

Gnomad NFE

AF:

0.312

Gnomad OTH

AF:

0.256

GnomAD4 exome

AF:

0.319

AC:

AN:

Hom.:

Cov.:

AF XY:

0.278

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.250

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.750

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.296

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.554

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.262

AC:

39936

AN:

152180

Hom.:

5614

Cov.:

AF XY:

0.259

AC XY:

19252

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.206

AC:

8557

AN:

41526

American (AMR)

AF:

0.227

AC:

3474

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.314

AC:

1089

AN:

3470

East Asian (EAS)

AF:

0.0741

AC:

384

AN:

5182

South Asian (SAS)

AF:

0.182

AC:

879

AN:

4826

European-Finnish (FIN)

AF:

0.323

AC:

3418

AN:

10596

Middle Eastern (MID)

AF:

0.236

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.312

AC:

21239

AN:

67970

Other (OTH)

AF:

0.254

AC:

536

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1489

2977

4466

5954

7443

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

420

840

1260

1680

2100

<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:

0.289

Hom.:

8250

Bravo

AF:

0.249

Asia WGS

AF:

0.137

AC:

476

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.69

(source)

DANN

Benign

0.56

PhyloP100

-0.74

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