9-27548435-GAAAAAAAAAAAAAAAA-GAAAAAA

Variant names:

• chr9-27548435-GAAAAAAAAAA-G
• rs11292923
• NM_018325.5:c.1260-23_1260-14delTTTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_018325.5(C9orf72):​c.1260-23_1260-14delTTTTTTTTTT variant causes a intron change. The variant allele was found at a frequency of 0.00215 in 174,878 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0036 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.15

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 9-27548435-GAAAAAAAAAA-G is Benign according to our data. Variant chr9-27548435-GAAAAAAAAAA-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00176 (243/138114) while in subpopulation AFR AF= 0.03 (93/3098). AF 95% confidence interval is 0.0251. There are 3 homozygotes in gnomad4_exome. There are 115 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 133 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.1260-23_1260-14delTTTTTTTTTT		intron_variant	Intron 10 of 10	ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.1260-23_1260-14delTTTTTTTTTT		intron_variant	Intron 10 of 10		NP_001242983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C9orf72	ENST00000380003.8	c.1260-23_1260-14delTTTTTTTTTT		intron_variant	Intron 10 of 10	1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.00362 AC: 133 AN: 36772 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000646

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00279

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000580

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00176 AC: 243 AN: 138114 Hom.: 3 AF XY: 0.00161 AC XY: 115 AN XY: 71370

Gnomad4 AFR exome AF: 0.0300

Gnomad4 AMR exome AF: 0.000177

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000743

Gnomad4 SAS exome AF: 0.00189

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00133

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00362 AC: 133 AN: 36764 Hom.: 0 Cov.: 0 AF XY: 0.00459 AC XY: 74 AN XY: 16132

Gnomad4 AFR AF: 0.0143

Gnomad4 AMR AF: 0.000645

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00280

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000580

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11292923; hg19: chr9-27548433;