Genetic Variant FAM9C:p.Glu31Lys (chrX-13043219-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_174901.6(FAM9C):c.91G>A(p.Glu31Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000207 in 1,206,303 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. 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: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000020 ( 0 hom. 9 hem. )

Consequence

FAM9C
NM_174901.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.127

Variant links:

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]

FAM9C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15460557).

BS2

High Hemizygotes in GnomAdExome4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM9C	NM_174901.6 link	c.91G>A	p.Glu31Lys	missense_variant	Exon 3 of 8	ENST00000380625.8	NP_777561.1	Q8IZT9A0A024RBW5
FAM9C	XM_024452348.2 link	c.403G>A	p.Glu135Lys	missense_variant	Exon 3 of 7		XP_024308116.2
FAM9C	XM_005274460.4 link	c.91G>A	p.Glu31Lys	missense_variant	Exon 3 of 8		XP_005274517.1	Q8IZT9A0A024RBW5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM9C	ENST00000380625.8 link	c.91G>A	p.Glu31Lys	missense_variant	Exon 3 of 8	1	NM_174901.6	ENSP00000369999.3		Q8IZT9

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112218

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34396

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000168

AC:

AN:

178123

Hom.:

AF XY:

0.0000318

AC XY:

AN XY:

62849

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000249

Gnomad OTH exome

AF:

0.000227

GnomAD4 exome

AF:

0.0000201

AC:

AN:

1094085

Hom.:

Cov.:

AF XY:

0.0000250

AC XY:

AN XY:

359739

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000262

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112218

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34396

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000564

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000169

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.91G>A (p.E31K) alteration is located in exon 3 (coding exon 2) of the FAM9C gene. This alteration results from a G to A substitution at nucleotide position 91, causing the glutamic acid (E) at amino acid position 31 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

0.11

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.83

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T;T

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.76

T;.;T

M_CAP

Benign

0.0031

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

.;L;L

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Benign

0.076

Sift

Pathogenic

0.0

D;T;T

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.88

.;P;P

Vest4

0.15

MutPred

0.25

Gain of ubiquitination at E31 (P = 0.0011);Gain of ubiquitination at E31 (P = 0.0011);Gain of ubiquitination at E31 (P = 0.0011);

MVP

0.74

MPC

0.044

ClinPred

0.57

GERP RS

-0.40

Varity_R

0.31

gMVP

0.074

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over