1-200111336-CAAAAAAA-CAAAAAAAAAA

Variant names:

• chr1-200111336-C-CAAA
• rs76894039
• NM_205860.3:c.1230+28_1230+30dupAAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_205860.3(NR5A2):​c.1230+28_1230+30dupAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00329 in 1,405,432 control chromosomes in the GnomAD database, including 67 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0082 (23 hom., cov: 27)
  • Exomes 𝑓: 0.0028 (44 hom.)
• Consequence: NR5A2 NM_205860.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.881
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00821 (1038/126472) while in subpopulation AFR AF = 0.0227 (791/34892). AF 95% confidence interval is 0.0214. There are 23 homozygotes in GnomAd4. There are 485 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1038 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_205860.3. 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
	NR5A2	NM_205860.3	MANE Select	c.1230+28_1230+30dupAAA		intron	N/A	NP_995582.1
	NR5A2	NM_003822.5		c.1092+28_1092+30dupAAA		intron	N/A	NP_003813.1
	NR5A2	NM_001276464.2		c.1014+28_1014+30dupAAA		intron	N/A	NP_001263393.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR5A2	ENST00000367362.8	TSL:1 MANE Select	c.1230+15_1230+16insAAA		intron	N/A	ENSP00000356331.3
	NR5A2	ENST00000236914.7	TSL:1	c.1092+15_1092+16insAAA		intron	N/A	ENSP00000236914.3
	NR5A2	ENST00000892175.1		c.1155+15_1155+16insAAA		intron	N/A	ENSP00000562234.1

Frequencies

GnomAD3 genomes AF: 0.00820 AC: 1037 AN: 126456 Hom.: 23 Cov.: 27

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.0445

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000417

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000825

Gnomad OTH AF: 0.00637

GnomAD2 exomes AF: 0.00539 AC: 551 AN: 102246 AF XY: 0.00493

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.00307

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.000604

Gnomad FIN exome AF: 0.00355

Gnomad NFE exome AF: 0.00480

Gnomad OTH exome AF: 0.00800

GnomAD4 exome AF: 0.00281 AC: 3592 AN: 1278960 Hom.: 44 Cov.: 0 AF XY: 0.00270 AC XY: 1710 AN XY: 633042

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0235 AC: 617 AN: 26208

American (AMR) AF: 0.00279 AC: 72 AN: 25834

Ashkenazi Jewish (ASJ) AF: 0.0209 AC: 417 AN: 20000

East Asian (EAS) AF: 0.000455 AC: 16 AN: 35196

South Asian (SAS) AF: 0.00126 AC: 85 AN: 67640

European-Finnish (FIN) AF: 0.00228 AC: 84 AN: 36904

Middle Eastern (MID) AF: 0.00303 AC: 14 AN: 4622

European-Non Finnish (NFE) AF: 0.00201 AC: 2025 AN: 1009788

Other (OTH) AF: 0.00497 AC: 262 AN: 52768

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00821 AC: 1038 AN: 126472 Hom.: 23 Cov.: 27 AF XY: 0.00798 AC XY: 485 AN XY: 60772

African (AFR) AF: 0.0227 AC: 791 AN: 34892

American (AMR) AF: 0.00359 AC: 46 AN: 12800

Ashkenazi Jewish (ASJ) AF: 0.0445 AC: 139 AN: 3122

East Asian (EAS) AF: 0.00 AC: 0 AN: 3942

South Asian (SAS) AF: 0.00 AC: 0 AN: 3724

European-Finnish (FIN) AF: 0.000417 AC: 3 AN: 7188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.000825 AC: 48 AN: 58174

Other (OTH) AF: 0.00637 AC: 11 AN: 1728

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.88
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs76894039; hg19: chr1-200080464;