14-44504976-T-C

Position:

• chr14-44504976-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032135.4(FSCB):​c.2012A>G​(p.Gln671Arg) variant causes a missense 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FSCB NM_032135.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.369

Genes affected

FSCB (HGNC:20494): (fibrous sheath CABYR binding protein) Predicted to enable calcium ion binding activity. Predicted to be involved in negative regulation of protein sumoylation. Predicted to be active in sperm fibrous sheath and sperm principal piece. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060061425).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FSCB	NM_032135.4	c.2012A>G	p.Gln671Arg	missense_variant	1/1	ENST00000340446.5	NP_115511.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FSCB	ENST00000340446.5	c.2012A>G	p.Gln671Arg	missense_variant	1/1		NM_032135.4	ENSP00000344579	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.88e-7 AC: 1 AN: 1453142 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 722656

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2024

The c.2012A>G (p.Q671R) alteration is located in exon 1 (coding exon 1) of the FSCB gene. This alteration results from a A to G substitution at nucleotide position 2012, causing the glutamine (Q) at amino acid position 671 to be replaced by an arginine (R). 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
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.2
DANN	Benign	0.76
DEOGEN2	Benign	0.010	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.014
Sift	Benign	0.26	T
Sift4G	Benign	0.21	T
Polyphen		0.089	B
Vest4		0.038
MutPred		0.22		Loss of glycosylation at P667 (P = 0.1628);
MVP		0.048
MPC		0.013
ClinPred		0.047	T
GERP RS		-5.8
Varity_R		0.039
gMVP		0.023

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-44974179;