1-200048714-C-G

Variant names:

• chr1-200048714-C-G
• rs777870204
• NM_205860.3:c.1006C>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_205860.3(NR5A2):​c.1006C>G​(p.His336Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: NR5A2 NM_205860.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.79

Genes affected

NR5A2 (HGNC:7984): (nuclear receptor subfamily 5 group A member 2) The protein encoded by this gene is a DNA-binding zinc finger transcription factor and is a member of the fushi tarazu factor-1 subfamily of orphan nuclear receptors. The encoded protein is involved in the expression of genes for hepatitis B virus and cholesterol biosynthesis, and may be an important regulator of embryonic development. [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.42175573).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR5A2	NM_205860.3	c.1006C>G	p.His336Asp	missense_variant	Exon 5 of 8	ENST00000367362.8	NP_995582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR5A2	ENST00000367362.8	c.1006C>G	p.His336Asp	missense_variant	Exon 5 of 8	1	NM_205860.3	ENSP00000356331.3
NR5A2	ENST00000236914.7	c.868C>G	p.His290Asp	missense_variant	Exon 4 of 7	1		ENSP00000236914.3
NR5A2	ENST00000367357.3	c.766C>G	p.His256Asp	missense_variant	Exon 3 of 4	1		ENSP00000356326.3
NR5A2	ENST00000544748.5	c.790C>G	p.His264Asp	missense_variant	Exon 4 of 7	2		ENSP00000439116.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251464 Hom.: 0 AF XY: 0.0000441 AC XY: 6 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461890 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 09, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1006C>G (p.H336D) alteration is located in exon 5 (coding exon 5) of the NR5A2 gene. This alteration results from a C to G substitution at nucleotide position 1006, causing the histidine (H) at amino acid position 336 to be replaced by an aspartic acid (D). 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	0.19
BayesDel_addAF	Benign	0.0079	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.42	T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.083	B;.;.
Vest4		0.67
MutPred		0.42		Gain of relative solvent accessibility (P = 0.0479);.;.;
MVP		0.72
MPC		0.60
ClinPred		0.22	T
GERP RS		4.4
Varity_R		0.79
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs777870204; hg19: chr1-200017842;