rs3849944

Positions:

• chr9-27560596-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_145005.7(C9orf72):​c.*985A>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 0.49 in 907,734 control chromosomes in the GnomAD database, including 109,672 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 0.46 (16307 hom., cov: 31)
  • Exomes 𝑓: 0.50 (93365 hom.)
• Consequence: C9orf72 NM_145005.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.244

Genes affected

C9orf72 (HGNC:28337): (C9orf72-SMCR8 complex subunit) The protein encoded by this gene plays an important role in the regulation of endosomal trafficking, and has been shown to interact with Rab proteins that are involved in autophagy and endocytic transport. Expansion of a GGGGCC repeat from 2-22 copies to 700-1600 copies in the intronic sequence between alternate 5' exons in transcripts from this gene is associated with 9p-linked ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia) (PMID: 21944778, 21944779). Studies suggest that hexanucleotide expansions could result in the selective stabilization of repeat-containing pre-mRNA, and the accumulation of insoluble dipeptide repeat protein aggregates that could be pathogenic in FTD-ALS patients (PMID: 23393093). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2016]

C9orf72 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.666-297A>G		intron_variant		ENST00000380003.8	NP_060795.1
C9orf72	NM_145005.7	c.*985A>G		3_prime_UTR_variant	5/5		NP_659442.2
C9orf72	NM_001256054.3	c.666-297A>G		intron_variant			NP_001242983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C9orf72	ENST00000380003.8	c.666-297A>G		intron_variant		1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69660 AN: 151650 Hom.: 16290 Cov.: 31

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.434

GnomAD4 exome AF: 0.496 AC: 374724 AN: 755966 Hom.: 93365 Cov.: 10 AF XY: 0.495 AC XY: 176022 AN XY: 355694

Gnomad4 AFR exome AF: 0.378

Gnomad4 AMR exome AF: 0.462

Gnomad4 ASJ exome AF: 0.418

Gnomad4 EAS exome AF: 0.409

Gnomad4 SAS exome AF: 0.511

Gnomad4 FIN exome AF: 0.563

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.477

GnomAD4 genome AF: 0.459 AC: 69707 AN: 151768 Hom.: 16307 Cov.: 31 AF XY: 0.458 AC XY: 33985 AN XY: 74164

Gnomad4 AFR AF: 0.383

Gnomad4 AMR AF: 0.449

Gnomad4 ASJ AF: 0.416

Gnomad4 EAS AF: 0.419

Gnomad4 SAS AF: 0.500

Gnomad4 FIN AF: 0.554

Gnomad4 NFE AF: 0.498

Gnomad4 OTH AF: 0.440

Alfa AF: 0.484 Hom.: 24408

Bravo AF: 0.448

Asia WGS AF: 0.497 AC: 1726 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.77

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

Other links and lift over

dbSNP: rs3849944; hg19: chr9-27560594;