NM_018325.5:c.-27G>A

Variant names:

• chr9-27567147-C-T
• rs10757668
• NM_018325.5:c.-27G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018325.5(C9orf72):​c.-27G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,583,956 control chromosomes in the GnomAD database, including 39,298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3228 hom., cov: 32)
  • Exomes 𝑓: 0.22 (36070 hom.)
• Consequence: C9orf72 NM_018325.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.293
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-27567147-C-T is Benign according to our data. Variant chr9-27567147-C-T is described in ClinVar as Benign. ClinVar VariationId is 366529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018325.5. 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.-27G>A		5_prime_UTR	Exon 2 of 11	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.-27G>A		5_prime_UTR	Exon 2 of 11	NP_001242983.1	Q96LT7-1
	C9orf72	NM_145005.7		c.-27G>A		5_prime_UTR	Exon 2 of 5	NP_659442.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9orf72	ENST00000380003.8	TSL:1 MANE Select	c.-27G>A		5_prime_UTR	Exon 2 of 11	ENSP00000369339.3	Q96LT7-1
	C9orf72	ENST00000619707.5	TSL:1	c.-27G>A		5_prime_UTR	Exon 2 of 11	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000644136.1		c.-27G>A		5_prime_UTR	Exon 2 of 12	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30424 AN: 151944 Hom.: 3223 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.185

GnomAD2 exomes AF: 0.199 AC: 48545 AN: 244534 AF XY: 0.203

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.111

Gnomad FIN exome AF: 0.246

Gnomad NFE exome AF: 0.232

Gnomad OTH exome AF: 0.205

GnomAD4 exome AF: 0.221 AC: 316404 AN: 1431894 Hom.: 36070 Cov.: 26 AF XY: 0.221 AC XY: 157195 AN XY: 712710

African (AFR) AF: 0.164 AC: 5399 AN: 32900

American (AMR) AF: 0.115 AC: 5097 AN: 44322

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 6392 AN: 25654

East Asian (EAS) AF: 0.102 AC: 4034 AN: 39474

South Asian (SAS) AF: 0.197 AC: 16864 AN: 85542

European-Finnish (FIN) AF: 0.242 AC: 12106 AN: 50026

Middle Eastern (MID) AF: 0.166 AC: 943 AN: 5684

European-Non Finnish (NFE) AF: 0.232 AC: 252801 AN: 1088862

Other (OTH) AF: 0.215 AC: 12768 AN: 59430

GnomAD4 genome AF: 0.200 AC: 30436 AN: 152062 Hom.: 3228 Cov.: 32 AF XY: 0.198 AC XY: 14733 AN XY: 74330

African (AFR) AF: 0.163 AC: 6763 AN: 41498

American (AMR) AF: 0.152 AC: 2322 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 871 AN: 3470

East Asian (EAS) AF: 0.111 AC: 574 AN: 5184

South Asian (SAS) AF: 0.194 AC: 933 AN: 4816

European-Finnish (FIN) AF: 0.238 AC: 2509 AN: 10550

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15901 AN: 67968

Other (OTH) AF: 0.188 AC: 396 AN: 2110

Alfa AF: 0.216 Hom.: 5576

Bravo AF: 0.188

Asia WGS AF: 0.178 AC: 617 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.3
DANN	Benign	0.72
PhyloP100		-0.29
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: 17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10757668; hg19: chr9-27567145; COSMIC: COSV66154683;