9-113423398-G-C

Variant names:

• chr9-113423398-G-C
• rs369164769
• NM_001278629.2:c.556G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001278629.2(C9orf43):​c.556G>C​(p.Val186Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V186M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: C9orf43 NM_001278629.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58
• Publications: 0 publications found

Genes affected

C9orf43 (HGNC:23570): (chromosome 9 open reading frame 43)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf43	NM_001278629.2	c.556G>C	p.Val186Leu	missense_variant	Exon 7 of 14	ENST00000374165.6	NP_001265558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C9orf43	ENST00000374165.6	c.556G>C	p.Val186Leu	missense_variant	Exon 7 of 14	1	NM_001278629.2	ENSP00000363280.1
C9orf43	ENST00000288462.4	c.556G>C	p.Val186Leu	missense_variant	Exon 7 of 14	1		ENSP00000288462.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111968

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.76	.;T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.7	L;L
PhyloP100		2.6
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.19
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.029	D;D
Polyphen		1.0	D;D
Vest4		0.61
MutPred		0.14		Gain of glycosylation at P187 (P = 0.1128);Gain of glycosylation at P187 (P = 0.1128);
MVP		0.45
MPC		0.38
ClinPred		0.84	D
GERP RS		4.0
Varity_R		0.17
gMVP		0.086
Mutation Taster		=98/2	polymorphism

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: rs369164769; hg19: chr9-116185678;