14-77406078-A-G

Variant names:

• chr14-77406078-A-G
• rs376956014
• NM_001113475.3:c.740T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001113475.3(NOXRED1):​c.740T>C​(p.Ile247Thr) 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. 17/22 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: NOXRED1 NM_001113475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.144
• Publications: 0 publications found

Genes affected

NOXRED1 (HGNC:20487): (NADP dependent oxidoreductase domain containing 1) Predicted to enable pyrroline-5-carboxylate reductase activity. Predicted to be involved in L-proline biosynthetic process. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047115326).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001113475.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOXRED1	NM_001113475.3	MANE Select	c.740T>C	p.Ile247Thr	missense	Exon 5 of 6	NP_001106946.1	Q6NXP6-1
	NOXRED1	NM_001394980.1		c.740T>C	p.Ile247Thr	missense	Exon 6 of 7	NP_001381909.1	Q6NXP6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOXRED1	ENST00000380835.7	TSL:1 MANE Select	c.740T>C	p.Ile247Thr	missense	Exon 5 of 6	ENSP00000370215.2	Q6NXP6-1
	NOXRED1	ENST00000555901.1	TSL:2	n.1495T>C		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000804 AC: 2 AN: 248712 AF XY: 0.00

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS 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

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000140 AC: 1

ExAC AF: 0.00000830 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.35
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.63	N
PhyloP100		0.14
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.12
Sift	Benign	0.47	T
Sift4G	Benign	0.52	T
Polyphen		0.0010	B
Vest4		0.11
MVP		0.16
MPC		0.18
ClinPred		0.34	T
GERP RS		-4.8
Varity_R		0.031
gMVP		0.50
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs376956014; hg19: chr14-77872421;