7-121351172-C-T

Variant names:

• chr7-121351172-C-T
• rs1046044727
• NM_014888.3:c.565G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014888.3(FAM3C):​c.565G>A​(p.Gly189Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G189R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FAM3C NM_014888.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.52
• Publications: 0 publications found

Genes affected

FAM3C (HGNC:18664): (FAM3 metabolism regulating signaling molecule C) This gene is a member of the family with sequence similarity 3 (FAM3) family and encodes a secreted protein with a GG domain. A change in expression of this protein has been noted in pancreatic cancer-derived cells. [provided by RefSeq, Mar 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014888.3. 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
	FAM3C	NM_014888.3	MANE Select	c.565G>A	p.Gly189Ser	missense	Exon 9 of 10	NP_055703.1	Q92520
	FAM3C	NM_001040020.2		c.565G>A	p.Gly189Ser	missense	Exon 9 of 10	NP_001035109.1	Q92520

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM3C	ENST00000359943.8	TSL:1 MANE Select	c.565G>A	p.Gly189Ser	missense	Exon 9 of 10	ENSP00000353025.3	Q92520
	FAM3C	ENST00000892193.1		c.616G>A	p.Gly206Ser	missense	Exon 10 of 11	ENSP00000562252.1
	FAM3C	ENST00000850865.1		c.565G>A	p.Gly189Ser	missense	Exon 9 of 10	ENSP00000520951.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251038 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461396 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726998

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111710

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.050	T
Polyphen		0.84	P
Vest4		0.92
MutPred		0.76		Gain of disorder (P = 0.1003)
MVP		0.71
MPC		1.3
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.62
gMVP		0.92
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs1046044727; hg19: chr7-120991226; COSMIC: COSV63436284;