10-47999702-C-T

Variant names:

• chr10-47999702-C-T
• rs80266306
• NM_001137548.3:c.64G>A

Variant summary

Our verdict is Likely benign. Variant got -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. 10/15 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.564

Genes affected

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

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.104962915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM25C	NM_001137548.3	c.64G>A	p.Glu22Lys	missense_variant	Exon 1 of 3	ENST00000617224.3	NP_001131020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM25C	ENST00000617224.3	c.64G>A	p.Glu22Lys	missense_variant	Exon 1 of 3	1	NM_001137548.3	ENSP00000485370.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 5 AN: 150614 Hom.: 0 Cov.: 20 FAILED QC

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: 32 AN: 1392488 Hom.: 0 Cov.: 31 AF XY: 0.0000233 AC XY: 16 AN XY: 686928

Gnomad4 AFR exome AF: 0.0000318

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000332 AC: 5 AN: 150614 Hom.: 0 Cov.: 20 AF XY: 0.0000136 AC XY: 1 AN XY: 73456

Gnomad4 AFR AF: 0.0000730

Gnomad4 AMR AF: 0.0000660

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.64G>A (p.E22K) alteration is located in exon 1 (coding exon 1) of the FAM25C gene. This alteration results from a G to A substitution at nucleotide position 64, causing the glutamic acid (E) at amino acid position 22 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	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.0091	N
M_CAP	Benign	0.00076	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.56	T
Sift4G	Benign	0.072	T
Vest4		0.17
MVP		0.040
ClinPred		0.25	T
GERP RS		0.57
Varity_R		0.12
gMVP		0.14

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

Other links and lift over

dbSNP: rs80266306; hg19: chr10-49207736;