X-13043755-A-T

Variant names:

• chrX-13043755-A-T
• NM_174901.6:c.35T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_174901.6(FAM9C):​c.35T>A​(p.Met12Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: FAM9C NM_174901.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0540

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19171926).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM9C	NM_174901.6	c.35T>A	p.Met12Lys	missense_variant	Exon 2 of 8	ENST00000380625.8	NP_777561.1
FAM9C	XM_024452348.2	c.347T>A	p.Met116Lys	missense_variant	Exon 2 of 7		XP_024308116.2
FAM9C	XM_005274460.4	c.35T>A	p.Met12Lys	missense_variant	Exon 2 of 8		XP_005274517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM9C	ENST00000380625.8	c.35T>A	p.Met12Lys	missense_variant	Exon 2 of 8	1	NM_174901.6	ENSP00000369999.3
FAM9C	ENST00000333995.7	c.35T>A	p.Met12Lys	missense_variant	Exon 2 of 7	1		ENSP00000334430.3
FAM9C	ENST00000542843.5	c.35T>A	p.Met12Lys	missense_variant	Exon 2 of 6	1		ENSP00000439185.1
FAM9C	ENST00000468287.1	n.245T>A		non_coding_transcript_exon_variant	Exon 2 of 7	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35T>A (p.M12K) alteration is located in exon 2 (coding exon 1) of the FAM9C gene. This alteration results from a T to A substitution at nucleotide position 35, causing the methionine (M) at amino acid position 12 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.1
DANN	Benign	0.55
DEOGEN2	Benign	0.10	T;T;T
FATHMM_MKL	Benign	0.0027	N
LIST_S2	Benign	0.43	T;.;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	.;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.8	D;N;N
REVEL	Benign	0.13
Sift	Benign	0.068	T;T;T
Sift4G	Benign	0.098	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.37
MutPred		0.25		Gain of ubiquitination at M12 (P = 0.0048);Gain of ubiquitination at M12 (P = 0.0048);Gain of ubiquitination at M12 (P = 0.0048);
MVP		0.77
MPC		0.013
ClinPred		0.073	T
GERP RS		-0.91
Varity_R		0.32
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-13061874;