rs774359

Variant names:

• chr9-27561051-T-C
• rs774359
• NM_018325.5:c.665+534A>G

Variant summary

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

The NM_145005.7(C9orf72):​c.*530A>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 0.232 in 179,578 control chromosomes in the GnomAD database, including 5,012 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 0.23 (4044 hom., cov: 32)
  • Exomes 𝑓: 0.26 (968 hom.)
• Consequence: C9orf72 NM_145005.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.296
• Publications: 51 publications found

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 Gene-Disease associations (from GenCC):

• frontotemporal dementia and/or amyotrophic lateral sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• progressive myoclonus epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145005.7. 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
	C9orf72	NM_018325.5	MANE Select	c.665+534A>G		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_145005.7		c.*530A>G		3_prime_UTR	Exon 5 of 5	NP_659442.2
	C9orf72	NM_001256054.3		c.665+534A>G		intron	N/A	NP_001242983.1	Q96LT7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9orf72	ENST00000380003.8	TSL:1 MANE Select	c.665+534A>G		intron	N/A	ENSP00000369339.3	Q96LT7-1
	C9orf72	ENST00000619707.5	TSL:1	c.665+534A>G		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000379997.7	TSL:2	c.*530A>G		3_prime_UTR	Exon 5 of 5	ENSP00000369333.3	Q96LT7-2

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34286 AN: 151818 Hom.: 4036 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.0953

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.235

GnomAD4 exome AF: 0.264 AC: 7298 AN: 27642 Hom.: 968 Cov.: 4 AF XY: 0.262 AC XY: 3552 AN XY: 13564

African (AFR) AF: 0.267 AC: 142 AN: 532

American (AMR) AF: 0.179 AC: 5 AN: 28

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 40 AN: 192

East Asian (EAS) AF: 0.102 AC: 13 AN: 128

South Asian (SAS) AF: 0.221 AC: 124 AN: 562

European-Finnish (FIN) AF: 0.0789 AC: 3 AN: 38

Middle Eastern (MID) AF: 0.294 AC: 20 AN: 68

European-Non Finnish (NFE) AF: 0.266 AC: 6698 AN: 25152

Other (OTH) AF: 0.269 AC: 253 AN: 942

GnomAD4 genome AF: 0.226 AC: 34320 AN: 151936 Hom.: 4044 Cov.: 32 AF XY: 0.222 AC XY: 16451 AN XY: 74260

African (AFR) AF: 0.225 AC: 9327 AN: 41444

American (AMR) AF: 0.185 AC: 2816 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 712 AN: 3470

East Asian (EAS) AF: 0.0954 AC: 494 AN: 5180

South Asian (SAS) AF: 0.207 AC: 998 AN: 4816

European-Finnish (FIN) AF: 0.167 AC: 1771 AN: 10574

Middle Eastern (MID) AF: 0.329 AC: 96 AN: 292

European-Non Finnish (NFE) AF: 0.255 AC: 17343 AN: 67890

Other (OTH) AF: 0.233 AC: 492 AN: 2110

Alfa AF: 0.245 Hom.: 18361

Bravo AF: 0.224

Asia WGS AF: 0.167 AC: 581 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.54
PhyloP100		-0.30
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: rs774359; hg19: chr9-27561049;