chr19-680361-C-A

Variant names:

• chr19-680361-C-A
• rs768914737
• NM_005860.3:c.377C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005860.3(FSTL3):​c.377C>A​(p.Ser126*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000886 in 1,128,794 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. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
• Consequence: FSTL3 NM_005860.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.57
• Publications: 0 publications found

Genes affected

FSTL3 (HGNC:3973): (follistatin like 3) Follistatin-like 3 is a secreted glycoprotein of the follistatin-module-protein family. It may have a role in leukemogenesis. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005860.3. 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
	FSTL3	NM_005860.3	MANE Select	c.377C>A	p.Ser126*	stop_gained	Exon 3 of 5	NP_005851.1	O95633-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FSTL3	ENST00000166139.9	TSL:1 MANE Select	c.377C>A	p.Ser126*	stop_gained	Exon 3 of 5	ENSP00000166139.3	O95633-1
	FSTL3	ENST00000905299.1		c.377C>A	p.Ser126*	stop_gained	Exon 3 of 4	ENSP00000575358.1
	FSTL3	ENST00000589185.2	TSL:2	c.44C>A	p.Ser15*	stop_gained	Exon 1 of 2	ENSP00000484376.1	A0A087X1Q2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.86e-7 AC: 1 AN: 1128794 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 541946

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

African (AFR) AF: 0.00 AC: 0 AN: 22820

American (AMR) AF: 0.00 AC: 0 AN: 8520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14800

East Asian (EAS) AF: 0.00 AC: 0 AN: 26184

South Asian (SAS) AF: 0.00 AC: 0 AN: 34808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3034

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 948556

Other (OTH) AF: 0.00 AC: 0 AN: 45442

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	36
DANN	Benign	0.97
Eigen	Benign	0.047
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.52	D
PhyloP100		3.6
Vest4		0.64
GERP RS		0.99
PromoterAI		-0.00030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=13/187	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs768914737; hg19: chr19-680361;