rs1048456

Variant names:

• chr5-141641152-T-G
• rs1048456
• NM_033449.3:c.*346A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033449.3(FCHSD1):​c.*346A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000059 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FCHSD1 NM_033449.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85
• Publications: 3 publications found

Genes affected

FCHSD1 (HGNC:25463): (FCH and double SH3 domains 1) Predicted to enable lipid binding activity. Predicted to be involved in neuromuscular synaptic transmission and positive regulation of actin filament polymerization. Predicted to be located in cell projection and perikaryon. Predicted to be active in neuromuscular junction and recycling endosome. Predicted to colocalize with cuticular plate. [provided by Alliance of Genome Resources, Apr 2022]

RELL2 (HGNC:26902): (RELT like 2) Predicted to enable collagen binding activity. Involved in positive regulation of p38MAPK cascade. Predicted to be located in extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCHSD1	NM_033449.3	c.*346A>C		3_prime_UTR_variant	Exon 20 of 20	ENST00000435817.7	NP_258260.1
RELL2	NM_173828.5	c.*483T>G		downstream_gene_variant		ENST00000297164.8	NP_776189.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCHSD1	ENST00000435817.7	c.*346A>C		3_prime_UTR_variant	Exon 20 of 20	1	NM_033449.3	ENSP00000399259.2
RELL2	ENST00000297164.8	c.*483T>G		downstream_gene_variant		1	NM_173828.5	ENSP00000297164.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000592 AC: 1 AN: 168932 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 85228

⚠️ 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: 5486

American (AMR) AF: 0.00 AC: 0 AN: 6992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6324

East Asian (EAS) AF: 0.00 AC: 0 AN: 14426

South Asian (SAS) AF: 0.00 AC: 0 AN: 3932

European-Finnish (FIN) AF: 0.0000858 AC: 1 AN: 11656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 892

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 107878

Other (OTH) AF: 0.00 AC: 0 AN: 11346

⚠️ 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.85
PhyloP100		1.9

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: rs1048456; hg19: chr5-141020719;