Genetic Variant FAM25C:p.Glu22Lys (chr10-47999702-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001137548.3(FAM25C):c.64G>A(p.Glu22Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. 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. E22Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 20)

Exomes 𝑓: 0.000023 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FAM25C
NM_001137548.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.564

Publications

1 publications found

Variant links:

Genes affected

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

FAM25C links:

ENSG00000304615 (HGNC:):

ENSG00000304615 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.104962915).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001137548.3. 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
	FAM25C	NM_001137548.3	MANE Select	c.64G>A	p.Glu22Lys	missense	Exon 1 of 3	NP_001131020.1	B3EWG5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM25C	ENST00000617224.3	TSL:1 MANE Select	c.64G>A	p.Glu22Lys	missense	Exon 1 of 3	ENSP00000485370.1	B3EWG5
	ENSG00000304615	ENST00000804955.1		n.175-10442C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000332

AC:

AN:

150614

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000730

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000230

AC:

AN:

1392488

Hom.:

Cov.:

AF XY:

0.0000233

AC XY:

AN XY:

686928

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000318

AC:

AN:

31448

American (AMR)

AF:

0.00

AC:

AN:

35308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25002

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79016

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48490

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4044

European-Non Finnish (NFE)

AF:

0.0000279

AC:

AN:

1075774

Other (OTH)

AF:

0.00

AC:

AN:

57668

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000444089), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.348

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000332

AC:

AN:

150614

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73456

show subpopulations

African (AFR)

AF:

0.0000730

AC:

AN:

41082

American (AMR)

AF:

0.0000660

AC:

AN:

15158

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67414

Other (OTH)

AF:

0.00

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.037

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.0091

M_CAP

Benign

0.00076

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.0

PhyloP100

0.56

PrimateAI

Uncertain

0.56

Sift4G

Benign

0.072

Vest4

0.17

MVP

0.040

ClinPred

0.25

GERP RS

0.57

PromoterAI

-0.0018

Neutral

(source)

Varity_R

0.12

gMVP

0.14

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over