chrX-13040870-C-T

Variant names:

• chrX-13040870-C-T
• rs368965856
• NM_174901.6:c.217G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_174901.6(FAM9C):​c.217G>A​(p.Asp73Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,126,163 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D73Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000071 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.0000079 (0 hom. 1 hem.)
• Consequence: FAM9C NM_174901.6 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92
• Publications: 0 publications found

Genes affected

FAM9C (HGNC:18405): (family with sequence similarity 9 member C) This gene is a member of a gene family which arose through duplication on the X chromosome. The encoded protein may be localized to the nucleus as the protein contains several nuclear localization signals, and has similarity to a synaptonemal complex protein. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1317923).
• BS2: High Hemizygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174901.6. 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
	FAM9C	NM_174901.6	MANE Select	c.217G>A	p.Asp73Asn	missense splice_region	Exon 5 of 8	NP_777561.1	Q8IZT9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM9C	ENST00000380625.8	TSL:1 MANE Select	c.217G>A	p.Asp73Asn	missense splice_region	Exon 5 of 8	ENSP00000369999.3	Q8IZT9
	FAM9C	ENST00000333995.7	TSL:1	c.217G>A	p.Asp73Asn	missense splice_region	Exon 5 of 7	ENSP00000334430.3	Q8IZT9
	FAM9C	ENST00000542843.5	TSL:1	c.*1875G>A		3_prime_UTR	Exon 4 of 6	ENSP00000439185.1	G3V1I3

Frequencies

GnomAD3 genomes AF: 0.0000713 AC: 8 AN: 112161 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000188

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000661

GnomAD2 exomes AF: 0.0000142 AC: 2 AN: 140889 AF XY: 0.00

Gnomad AFR exome AF: 0.000174

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000789 AC: 8 AN: 1013951 Hom.: 0 Cov.: 20 AF XY: 0.00000337 AC XY: 1 AN XY: 297151

African (AFR) AF: 0.0000838 AC: 2 AN: 23866

American (AMR) AF: 0.0000743 AC: 2 AN: 26914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17942

East Asian (EAS) AF: 0.00 AC: 0 AN: 28701

South Asian (SAS) AF: 0.00 AC: 0 AN: 43456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3048

European-Non Finnish (NFE) AF: 0.00000127 AC: 1 AN: 787850

Other (OTH) AF: 0.0000700 AC: 3 AN: 42872

GnomAD4 genome AF: 0.0000713 AC: 8 AN: 112212 Hom.: 0 Cov.: 23 AF XY: 0.0000581 AC XY: 2 AN XY: 34412

African (AFR) AF: 0.000162 AC: 5 AN: 30930

American (AMR) AF: 0.000188 AC: 2 AN: 10657

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3617

South Asian (SAS) AF: 0.00 AC: 0 AN: 2742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53231

Other (OTH) AF: 0.000652 AC: 1 AN: 1533

Alfa AF: 0.0000869 Hom.: 1

Bravo AF: 0.000238

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.075
Sift	Benign	0.037	D
Sift4G	Benign	0.56	T
Polyphen		0.98	D
Vest4		0.46
MVP		0.33
MPC		0.061
ClinPred		0.23	T
GERP RS		0.59
Varity_R		0.14
gMVP		0.27
Mutation Taster		=91/9	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: rs368965856; hg19: chrX-13058989;