chr15-82759374-T-G

Variant names:

• chr15-82759374-T-G
• rs201393187
• NM_001007122.4:c.2224A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001007122.4(FSD2):​c.2224A>C​(p.Met742Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. M742V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FSD2 NM_001007122.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.280
• Publications: 0 publications found

Genes affected

FSD2 (HGNC:18024): (fibronectin type III and SPRY domain containing 2) This gene encodes a protein that belongs to the FN3/SPRY family of proteins. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

SNHG21 (HGNC:50284): (small nucleolar RNA host gene 21)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12271106).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001007122.4. 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
	FSD2	NM_001007122.4	MANE Select	c.2224A>C	p.Met742Leu	missense	Exon 13 of 13	NP_001007123.1	A1L4K1-1
	FSD2	NM_001281805.2		c.2089A>C	p.Met697Leu	missense	Exon 13 of 13	NP_001268734.1	A1L4K1-2
	FSD2	NM_001281806.2		c.2089A>C	p.Met697Leu	missense	Exon 12 of 12	NP_001268735.1	A1L4K1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FSD2	ENST00000334574.12	TSL:1 MANE Select	c.2224A>C	p.Met742Leu	missense	Exon 13 of 13	ENSP00000335651.8	A1L4K1-1
	FSD2	ENST00000541889.1	TSL:1	c.2089A>C	p.Met697Leu	missense	Exon 12 of 12	ENSP00000444078.1	A1L4K1-2
	FSD2	ENST00000961201.1		c.2224A>C	p.Met742Leu	missense	Exon 14 of 14	ENSP00000631260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461070 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726772

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111666

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	11
DANN	Benign	0.67
DEOGEN2	Benign	0.0098	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.28
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.038
Sift	Benign	0.35	T
Sift4G	Benign	0.20	T
Polyphen		0.012	B
Vest4		0.25
MutPred		0.50		Loss of ubiquitination at K744 (P = 0.0811)
MVP		0.092
MPC		0.050
ClinPred		0.19	T
GERP RS		0.36
Varity_R		0.14
gMVP		0.27
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs201393187; hg19: chr15-83428126;