chr9-124482806-C-T

Position:

• chr9-124482806-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004959.5(NR5A1):​c.1338G>A​(p.Met446Ile) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: NR5A1 NM_004959.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51

Genes affected

NR5A1 (HGNC:7983): (nuclear receptor subfamily 5 group A member 1) The protein encoded by this gene is a transcriptional activator involved in sex determination. The encoded protein binds DNA as a monomer. Defects in this gene are a cause of XY sex reversal with or without adrenal failure as well as adrenocortical insufficiency without ovarian defect. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3064186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR5A1	NM_004959.5	c.1338G>A	p.Met446Ile	missense_variant	7/7	ENST00000373588.9	NP_004950.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR5A1	ENST00000373588.9	c.1338G>A	p.Met446Ile	missense_variant	7/7	1	NM_004959.5	ENSP00000362690.4
NR5A1	ENST00000620110.4	c.1218G>A	p.Met406Ile	missense_variant	6/6	5		ENSP00000483309.1
NR5A1	ENST00000373587.3	c.690G>A	p.Met230Ile	missense_variant	5/5	3		ENSP00000362689.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2024

The c.1338G>A (p.M446I) alteration is located in exon 7 (coding exon 6) of the NR5A1 gene. This alteration results from a G to A substitution at nucleotide position 1338, causing the methionine (M) at amino acid position 446 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	0.28
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	.;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.091
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	-0.34	.;N;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.57	.;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.031	.;D;D
Sift4G	Benign	0.13	T;T;D
Polyphen		0.0040	.;B;.
Vest4		0.33
MutPred		0.48		.;Gain of catalytic residue at L451 (P = 0.0377);.;
MVP		0.39
MPC		0.83
ClinPred		0.85	D
GERP RS		3.9
Varity_R		0.66
gMVP		0.10

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: chr9-127245085;