NM_199350.4:c.575A>G

Variant names:

• chr9-129619764-T-C
• rs139758889
• NM_199350.4:c.575A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_199350.4(C9orf50):​c.575A>G​(p.Asn192Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,613,656 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0036 (18 hom.)
• Consequence: C9orf50 NM_199350.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.41
• Publications: 8 publications found

Genes affected

C9orf50 (HGNC:23677): (chromosome 9 open reading frame 50)

NTMT1 (HGNC:23373): (N-terminal Xaa-Pro-Lys N-methyltransferase 1) The METTL11A gene encodes an N-terminal methyltransferase for the RAN (MIM 601179) guanine nucleotide exchange factor regulator of chromosome condensation 1 (RCC1; MIM 179710). METTL11A enzyme alpha-N-methylates other protein targets such as SET (MIM 600960) and RB (MIM 180200).[supplied by OMIM, Nov 2010]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034188926).
• BP6: Variant 9-129619764-T-C is Benign according to our data. Variant chr9-129619764-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2659571.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199350.4. 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
	C9orf50	NM_199350.4	MANE Select	c.575A>G	p.Asn192Ser	missense	Exon 2 of 7	NP_955382.3	Q5SZB4
	NTMT1	NM_001286796.2		c.-55+10586T>C		intron	N/A	NP_001273725.1	Q9BV86-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9orf50	ENST00000372478.5	TSL:2 MANE Select	c.575A>G	p.Asn192Ser	missense	Exon 2 of 7	ENSP00000361556.4	Q5SZB4
	C9orf50	ENST00000619117.1	TSL:1	c.-368+839A>G		intron	N/A	ENSP00000480795.1	A0A087WX76
	NTMT1	ENST00000372486.5	TSL:5	c.-55+10586T>C		intron	N/A	ENSP00000361564.1	Q9BV86-1

Frequencies

GnomAD3 genomes AF: 0.00315 AC: 478 AN: 151656 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000849

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00605

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00251

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00439

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00324 AC: 815 AN: 251470 AF XY: 0.00335

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00384

Gnomad ASJ exome AF: 0.00694

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00425

Gnomad OTH exome AF: 0.00700

GnomAD4 exome AF: 0.00364 AC: 5314 AN: 1461882 Hom.: 18 Cov.: 33 AF XY: 0.00356 AC XY: 2588 AN XY: 727246

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00425 AC: 190 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00681 AC: 178 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00259 AC: 223 AN: 86258

European-Finnish (FIN) AF: 0.000374 AC: 20 AN: 53416

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5768

European-Non Finnish (NFE) AF: 0.00392 AC: 4360 AN: 1112004

Other (OTH) AF: 0.00430 AC: 260 AN: 60396

GnomAD4 genome AF: 0.00315 AC: 478 AN: 151774 Hom.: 2 Cov.: 31 AF XY: 0.00291 AC XY: 216 AN XY: 74196

African (AFR) AF: 0.000846 AC: 35 AN: 41370

American (AMR) AF: 0.00604 AC: 92 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 26 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00251 AC: 12 AN: 4776

European-Finnish (FIN) AF: 0.000284 AC: 3 AN: 10560

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00439 AC: 298 AN: 67932

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00434 Hom.: 7

Bravo AF: 0.00346

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00308 AC: 374

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.98
DANN	Benign	0.59
DEOGEN2	Benign	0.00093	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.46	N
PhyloP100		-1.4
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.019
Sift	Benign	0.92	T
Sift4G	Benign	0.65	T
Polyphen		0.010	B
Vest4		0.063
MVP		0.014
MPC		0.53
ClinPred		0.00099	T
GERP RS		-6.2
PromoterAI		0.030	Neutral
Varity_R		0.030
gMVP		0.012
Mutation Taster		=100/0	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: rs139758889; hg19: chr9-132382043; COSMIC: COSV105299907; COSMIC: COSV105299907;