1-48727938-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024603.4(BEND5):c.1214A>G(p.Asn405Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,652 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BEND5 NM_024603.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63

Genes affected

BEND5 (HGNC:25668): (BEN domain containing 5) Predicted to enable DNA binding activity. Involved in negative regulation of transcription, DNA-templated. Predicted to be located in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

AGBL4 (HGNC:25892): (AGBL carboxypeptidase 4) Predicted to enable metallocarboxypeptidase activity and tubulin binding activity. Predicted to be involved in C-terminal protein deglutamylation; defense response to virus; and protein side chain deglutamylation. Predicted to act upstream of or within several processes, including axonal transport of mitochondrion; positive regulation of ubiquitin-dependent protein catabolic process; and regulation of blastocyst development. Located in Golgi apparatus; centriole; and ciliary basal body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BEND5	NM_024603.4	c.1214A>G	p.Asn405Ser	missense_variant	6/6	ENST00000371833.4
AGBL4	NM_032785.4	c.635-64697A>G		intron_variant		ENST00000371839.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BEND5	ENST00000371833.4	c.1214A>G	p.Asn405Ser	missense_variant	6/6	1	NM_024603.4	P1
AGBL4	ENST00000371839.6	c.635-64697A>G		intron_variant		2	NM_032785.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459652 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726068

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jul 11, 2022

The c.1214A>G (p.N405S) alteration is located in exon 6 (coding exon 6) of the BEND5 gene. This alteration results from a A to G substitution at nucleotide position 1214, causing the asparagine (N) at amino acid position 405 to be replaced by a serine (S). 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	Pathogenic	0.96
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.26
Sift	Benign	0.24	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.11		Loss of helix (P = 0.0558);
MVP		0.54
MPC		1.5
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.20
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs1317739667; hg19: chr1-49193610;