rs8074444

Variant names:

• chr17-18321464-C-T
• rs8074444
• NM_144775.3:c.2361-1153C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_144775.3(SMCR8):​c.2361-1153C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 152,096 control chromosomes in the GnomAD database, including 13,234 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 0.39 (13234 hom., cov: 33)
• Consequence: SMCR8 NM_144775.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.568
• Publications: 5 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCR8	NM_144775.3	c.2361-1153C>T		intron_variant	Intron 1 of 1	ENST00000406438.5	NP_658988.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCR8	ENST00000406438.5	c.2361-1153C>T		intron_variant	Intron 1 of 1	1	NM_144775.3	ENSP00000385025.3

Frequencies

GnomAD3 genomes AF: 0.389 AC: 59047 AN: 151978 Hom.: 13197 Cov.: 33

Gnomad AFR AF: 0.614

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.0776

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.366

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.389 AC: 59143 AN: 152096 Hom.: 13234 Cov.: 33 AF XY: 0.382 AC XY: 28410 AN XY: 74362

African (AFR) AF: 0.615 AC: 25511 AN: 41492

American (AMR) AF: 0.291 AC: 4443 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1252 AN: 3470

East Asian (EAS) AF: 0.0782 AC: 405 AN: 5178

South Asian (SAS) AF: 0.199 AC: 958 AN: 4820

European-Finnish (FIN) AF: 0.325 AC: 3438 AN: 10576

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.323 AC: 21961 AN: 67962

Other (OTH) AF: 0.367 AC: 774 AN: 2110

Alfa AF: 0.382 Hom.: 1531

Bravo AF: 0.393

Asia WGS AF: 0.191 AC: 666 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.3
DANN	Benign	0.36
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8074444; hg19: chr17-18224778; COSMIC: COSV68810749;