14-52007949-G-C

Position:

• chr14-52007949-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007361.4(NID2):​c.3741C>G​(p.Asp1247Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NID2 NM_007361.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.01

Genes affected

NID2 (HGNC:13389): (nidogen 2) This gene encodes a member of the nidogen family of basement membrane proteins. This protein is a cell-adhesion protein that binds collagens I and IV and laminin and may be involved in maintaining the structure of the basement membrane.[provided by RefSeq, Jun 2010]

RTRAF (HGNC:23169): (RNA transcription, translation and transport factor) Enables RNA binding activity; RNA polymerase II complex binding activity; and identical protein binding activity. Involved in negative regulation of protein kinase activity; positive regulation of transcription by RNA polymerase II; and tRNA splicing, via endonucleolytic cleavage and ligation. Located in microtubule cytoskeleton; nucleoplasm; and perinuclear region of cytoplasm. Part of tRNA-splicing ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NID2	NM_007361.4	c.3741C>G	p.Asp1247Glu	missense_variant	19/22	ENST00000216286.10	NP_031387.3
RTRAF	NM_016039.3	c.*3433G>C		3_prime_UTR_variant	8/8	ENST00000261700.8	NP_057123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NID2	ENST00000216286.10	c.3741C>G	p.Asp1247Glu	missense_variant	19/22	1	NM_007361.4	ENSP00000216286	P1
RTRAF	ENST00000261700.8	c.*3433G>C		3_prime_UTR_variant	8/8	1	NM_016039.3	ENSP00000261700	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Oct 12, 2022

The c.3741C>G (p.D1247E) alteration is located in exon 19 (coding exon 19) of the NID2 gene. This alteration results from a C to G substitution at nucleotide position 3741, causing the aspartic acid (D) at amino acid position 1247 to be replaced by a glutamic acid (E). 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	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	-0.097	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.72	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.82		Gain of catalytic residue at L1243 (P = 0);.;
MVP		0.93
MPC		0.47
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.86
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr14-52474667;