14-55151941-C-T

Variant names:

• chr14-55151941-C-T
• rs1882034570
• NM_014750.5:c.2122G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014750.5(DLGAP5):​c.2122G>A​(p.Val708Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DLGAP5 NM_014750.5 missense, splice_region
• Scores: Splicing: ADA: 0.001273
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69

Genes affected

DLGAP5 (HGNC:16864): (DLG associated protein 5) Predicted to enable microtubule binding activity. Predicted to be involved in several processes, including centrosome localization; kinetochore assembly; and mitotic spindle organization. Located in several cellular components, including centrosome; cytosol; and mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07949647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLGAP5	NM_014750.5	c.2122G>A	p.Val708Ile	missense_variant, splice_region_variant	Exon 17 of 19	ENST00000247191.7	NP_055565.3
DLGAP5	NM_001146015.2	c.2122G>A	p.Val708Ile	missense_variant, splice_region_variant	Exon 17 of 20		NP_001139487.1
DLGAP5	XM_017021840.3	c.2122G>A	p.Val708Ile	missense_variant, splice_region_variant	Exon 17 of 19		XP_016877329.1
DLGAP5	XM_047432016.1	c.2122G>A	p.Val708Ile	missense_variant, splice_region_variant	Exon 17 of 20		XP_047287972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLGAP5	ENST00000247191.7	c.2122G>A	p.Val708Ile	missense_variant, splice_region_variant	Exon 17 of 19	1	NM_014750.5	ENSP00000247191.2
DLGAP5	ENST00000395425.6	c.2122G>A	p.Val708Ile	missense_variant, splice_region_variant	Exon 17 of 20	1		ENSP00000378815.2
DLGAP5	ENST00000554007.1	n.56G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452390 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721864

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.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2122G>A (p.V708I) alteration is located in exon 17 (coding exon 16) of the DLGAP5 gene. This alteration results from a G to A substitution at nucleotide position 2122, causing the valine (V) at amino acid position 708 to be replaced by an isoleucine (I). 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	0.079
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	13
DANN	Benign	0.84
DEOGEN2	Benign	0.050	.;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.079	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.15	N;N
REVEL	Benign	0.036
Sift	Benign	0.058	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.046	.;B
Vest4		0.15
MutPred		0.23		Gain of catalytic residue at V709 (P = 0.1133);Gain of catalytic residue at V709 (P = 0.1133);
MVP		0.12
MPC		0.055
ClinPred		0.082	T
GERP RS		1.1
Varity_R		0.018
gMVP		0.035

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.11
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: rs1882034570; hg19: chr14-55618659;