Genetic Variant FAM25C:p.Glu67Lys (chr10-47995449-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_001137548.3(FAM25C):c.199G>A(p.Glu67Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,527,368 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000059 ( 2 hom. )

Consequence

FAM25C
NM_001137548.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.507

Variant links:

Genes affected

FAM25C (HGNC:23586): (family with sequence similarity 25 member C)

FAM25C 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=0.10911226).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM25C	NM_001137548.3 link	c.199G>A	p.Glu67Lys	missense_variant	Exon 3 of 3	ENST00000617224.3	NP_001131020.1	B3EWG3B3EWG5B3EWG6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM25C	ENST00000617224.3 link	c.199G>A	p.Glu67Lys	missense_variant	Exon 3 of 3	1	NM_001137548.3	ENSP00000485370.1		B3EWG5

Frequencies

GnomAD3 genomes

AF:

0.0000600

AC:

AN:

150058

Hom.:

Cov.:

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:

0.000384

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000744

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000895

AC:

AN:

145182

Hom.:

AF XY:

0.0000259

AC XY:

AN XY:

77196

show subpopulations

Gnomad AFR exome

AF:

0.000253

Gnomad AMR exome

AF:

0.0000410

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.000151

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000588

AC:

AN:

1377202

Hom.:

Cov.:

AF XY:

0.0000559

AC XY:

AN XY:

679862

show subpopulations

Gnomad4 AFR exome

AF:

0.0000637

Gnomad4 AMR exome

AF:

0.0000563

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000253

Gnomad4 FIN exome

AF:

0.000511

Gnomad4 NFE exome

AF:

0.0000531

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000599

AC:

AN:

150166

Hom.:

Cov.:

AF XY:

0.0000819

AC XY:

AN XY:

73264

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:

0.000384

Gnomad4 NFE

AF:

0.0000744

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.199G>A (p.E67K) alteration is located in exon 3 (coding exon 3) of the FAM25C gene. This alteration results from a G to A substitution at nucleotide position 199, causing the glutamic acid (E) at amino acid position 67 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

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.081

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.020

M_CAP

Benign

0.00088

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.57

Sift4G

Benign

0.14

Vest4

0.19

MVP

0.055

ClinPred

0.076

GERP RS

0.35

Varity_R

0.13

gMVP

0.093

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