5-111730929-A-G

Position:

• chr5-111730929-A-G

Variant summary

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

The NM_004772.4(NREP):​c.199T>C​(p.Phe67Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NREP NM_004772.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.730

Genes affected

NREP (HGNC:16834): (neuronal regeneration related protein) Predicted to be involved in axon regeneration; regulation of neuron differentiation; and regulation of transforming growth factor beta receptor signaling pathway. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

STARD4-AS1 (HGNC:44117): (STARD4 antisense RNA 1)

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=0.085178286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NREP	NM_004772.4	c.199T>C	p.Phe67Leu	missense_variant	4/4	ENST00000257435.12
STARD4-AS1	NR_040093.1	n.1037-852A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NREP	ENST00000257435.12	c.199T>C	p.Phe67Leu	missense_variant	4/4	1	NM_004772.4	P1
STARD4-AS1	ENST00000500779.2	n.1037-852A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Feb 04, 2022

The c.331T>C (p.F111L) alteration is located in exon 4 (coding exon 4) of the NREP gene. This alteration results from a T to C substitution at nucleotide position 331, causing the phenylalanine (F) at amino acid position 111 to be replaced by a leucine (L). 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T;T;T;T;.;T;T;T;T;T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.48	.;.;T;.;T;.;.;.;.;.;.
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.085	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.046
Sift	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0040	B;B;B;B;.;B;B;B;B;B;B
Vest4		0.027
MutPred		0.28		Gain of catalytic residue at F67 (P = 0.0845);Gain of catalytic residue at F67 (P = 0.0845);Gain of catalytic residue at F67 (P = 0.0845);Gain of catalytic residue at F67 (P = 0.0845);.;Gain of catalytic residue at F67 (P = 0.0845);Gain of catalytic residue at F67 (P = 0.0845);Gain of catalytic residue at F67 (P = 0.0845);Gain of catalytic residue at F67 (P = 0.0845);Gain of catalytic residue at F67 (P = 0.0845);Gain of catalytic residue at F67 (P = 0.0845);
MVP		0.18
MPC		0.23
ClinPred		0.69	D
GERP RS		1.4
Varity_R		0.046
gMVP		0.093

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-111066626;