9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAAAAAAAAAAAAAA

Variant names:

• chr9-27548435-G-GAAAAAAAA
• rs11292923
• NM_018325.5:c.1260-21_1260-14dupTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_018325.5(C9orf72):​c.1260-21_1260-14dupTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0098 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0051 (9 hom.)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.242

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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00506 (699/138086) while in subpopulation SAS AF= 0.0184 (146/7942). AF 95% confidence interval is 0.016. There are 9 homozygotes in gnomad4_exome. There are 403 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 361 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.1260-21_1260-14dupTTTTTTTT		intron_variant	Intron 10 of 10	ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.1260-21_1260-14dupTTTTTTTT		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.1260-14_1260-13insTTTTTTTT		intron_variant	Intron 10 of 10	1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.00982 AC: 361 AN: 36770 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00870

Gnomad AMI AF: 0.00287

Gnomad AMR AF: 0.00388

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00480

Gnomad SAS AF: 0.00698

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.0122

GnomAD4 exome AF: 0.00506 AC: 699 AN: 138086 Hom.: 9 Cov.: 0 AF XY: 0.00565 AC XY: 403 AN XY: 71356

Gnomad4 AFR exome AF: 0.00484

Gnomad4 AMR exome AF: 0.00636

Gnomad4 ASJ exome AF: 0.00403

Gnomad4 EAS exome AF: 0.00163

Gnomad4 SAS exome AF: 0.0184

Gnomad4 FIN exome AF: 0.00484

Gnomad4 NFE exome AF: 0.00442

Gnomad4 OTH exome AF: 0.00490

GnomAD4 genome AF: 0.00982 AC: 361 AN: 36762 Hom.: 0 Cov.: 0 AF XY: 0.00949 AC XY: 153 AN XY: 16130

Gnomad4 AFR AF: 0.00869

Gnomad4 AMR AF: 0.00387

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00482

Gnomad4 SAS AF: 0.00700

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.0122

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;