chr14-44504956-C-T

Variant names:

• chr14-44504956-C-T
• rs777894410
• NM_032135.4:c.2032G>A

Variant summary

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

The NM_032135.4(FSCB):​c.2032G>A​(p.Ala678Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,032 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A678D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FSCB NM_032135.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.01
• Publications: 0 publications found

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]

LINC02277 (HGNC:53193): (long intergenic non-protein coding RNA 2277)

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 (MetaRNN=0.05850166).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032135.4. 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
	FSCB	NM_032135.4	MANE Select	c.2032G>A	p.Ala678Thr	missense	Exon 1 of 1	NP_115511.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FSCB	ENST00000340446.5	TSL:6 MANE Select	c.2032G>A	p.Ala678Thr	missense	Exon 1 of 1	ENSP00000344579.4	Q5H9T9
	LINC02277	ENST00000557721.2	TSL:2	n.108-60134G>A		intron	N/A
	LINC02277	ENST00000795526.1		n.108-60134G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455032 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723802

African (AFR) AF: 0.00 AC: 0 AN: 32414

American (AMR) AF: 0.00 AC: 0 AN: 44340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39292

South Asian (SAS) AF: 0.00 AC: 0 AN: 85530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4544

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109854

Other (OTH) AF: 0.00 AC: 0 AN: 59882

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.79
DANN	Benign	0.90
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		-1.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.034
Sift	Benign	0.24	T
Sift4G	Benign	0.36	T
Polyphen		0.85	P
Vest4		0.057
MutPred		0.18		Gain of phosphorylation at A678 (P = 0.0058)
MVP		0.072
MPC		0.013
ClinPred		0.18	T
GERP RS		-1.8
Varity_R		0.031
gMVP		0.041
Mutation Taster		=99/1	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: rs777894410; hg19: chr14-44974159;