NM_001009931.3:c.6654G>A

Variant names:

• chr1-152214975-C-T
• rs144369469
• NM_001009931.3:c.6654G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_001009931.3(HRNR):​c.6654G>A​(p.Ser2218Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S2218S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (4 hom., cov: 37)
  • Exomes 𝑓: 0.011 (15 hom.)
  • Failed GnomAD Quality Control
• Consequence: HRNR NM_001009931.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.08
• Publications: 3 publications found

Genes affected

HRNR (HGNC:20846): (hornerin) Predicted to enable calcium ion binding activity and transition metal ion binding activity. Involved in cell envelope organization and establishment of skin barrier. Located in cornified envelope; keratohyalin granule; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CCDST (HGNC:55988): (cervical cancer associated DHX9 suppressive transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP7: Synonymous conserved (PhyloP=-2.08 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009931.3. 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
	HRNR	NM_001009931.3	MANE Select	c.6654G>A	p.Ser2218Ser	synonymous	Exon 3 of 3	NP_001009931.1	Q86YZ3
	CCDST	NR_186761.1		n.353+25320C>T		intron	N/A
	CCDST	NR_186762.1		n.179+25494C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRNR	ENST00000368801.4	TSL:1 MANE Select	c.6654G>A	p.Ser2218Ser	synonymous	Exon 3 of 3	ENSP00000357791.3	Q86YZ3
	CCDST	ENST00000420707.5	TSL:5	n.158+25467C>T		intron	N/A
	CCDST	ENST00000593011.5	TSL:4	n.296+46555C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1589 AN: 142418 Hom.: 4 Cov.: 37

Gnomad AFR AF: 0.00334

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.0161

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.00455

Gnomad MID AF: 0.0234

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.0118

GnomAD2 exomes AF: 0.0148 AC: 1174 AN: 79386 AF XY: 0.0150

Gnomad AFR exome AF: 0.00374

Gnomad AMR exome AF: 0.0146

Gnomad ASJ exome AF: 0.0151

Gnomad EAS exome AF: 0.0123

Gnomad FIN exome AF: 0.00603

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0170

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0109 AC: 15377 AN: 1412758 Hom.: 15 Cov.: 119 AF XY: 0.0115 AC XY: 8047 AN XY: 702422

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

African (AFR) AF: 0.00306 AC: 101 AN: 33052

American (AMR) AF: 0.00728 AC: 320 AN: 43946

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 305 AN: 25626

East Asian (EAS) AF: 0.0305 AC: 1133 AN: 37166

South Asian (SAS) AF: 0.0253 AC: 2063 AN: 81698

European-Finnish (FIN) AF: 0.00440 AC: 231 AN: 52552

Middle Eastern (MID) AF: 0.0182 AC: 102 AN: 5592

European-Non Finnish (NFE) AF: 0.00979 AC: 10517 AN: 1074550

Other (OTH) AF: 0.0103 AC: 605 AN: 58576

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0111 AC: 1585 AN: 142544 Hom.: 4 Cov.: 37 AF XY: 0.0111 AC XY: 775 AN XY: 69692

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

African (AFR) AF: 0.00332 AC: 122 AN: 36696

American (AMR) AF: 0.0140 AC: 202 AN: 14472

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 45 AN: 3386

East Asian (EAS) AF: 0.0161 AC: 75 AN: 4646

South Asian (SAS) AF: 0.0316 AC: 140 AN: 4432

European-Finnish (FIN) AF: 0.00455 AC: 47 AN: 10338

Middle Eastern (MID) AF: 0.0207 AC: 5 AN: 242

European-Non Finnish (NFE) AF: 0.0138 AC: 905 AN: 65498

Other (OTH) AF: 0.0112 AC: 22 AN: 1966

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00636 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.8
DANN	Benign	0.62
PhyloP100		-2.1
Mutation Taster		=100/0	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: rs144369469; hg19: chr1-152187451;