14-52006627-C-T

Variant names:

• chr14-52006627-C-T
• rs375705872
• NM_007361.4:c.3914G>A

Variant summary

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

The NM_007361.4(NID2):​c.3914G>A​(p.Gly1305Glu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1305A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NID2 NM_007361.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.00

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, 0.843

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NID2	NM_007361.4	c.3914G>A	p.Gly1305Glu	missense_variant	Exon 20 of 22	ENST00000216286.10	NP_031387.3
RTRAF	NM_016039.3	c.*2111C>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000261700.8	NP_057123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NID2	ENST00000216286.10	c.3914G>A	p.Gly1305Glu	missense_variant	Exon 20 of 22	1	NM_007361.4	ENSP00000216286.4
RTRAF	ENST00000261700.8	c.*2111C>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_016039.3	ENSP00000261700.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251402 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	4.0	H;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.014	D;.
Sift4G	Benign	0.27	T;T
Polyphen		0.99	D;.
Vest4		0.87
MutPred		0.65		Gain of catalytic residue at R1309 (P = 0.024);.;
MVP		0.65
MPC		0.53
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.74
gMVP		0.92

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: rs375705872; hg19: chr14-52473345;