1-152216385-C-T

Variant names:

• chr1-152216385-C-T
• rs201735593
• NM_001009931.3:c.5244G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001009931.3(HRNR):​c.5244G>A​(p.Ser1748Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 144,170 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S1748S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 55)
  • Exomes 𝑓: 0.000072 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HRNR NM_001009931.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.07
• Publications: 0 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP7: Synonymous conserved (PhyloP=-3.07 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.5244G>A	p.Ser1748Ser	synonymous	Exon 3 of 3	NP_001009931.1	Q86YZ3
	CCDST	NR_186761.1		n.353+26730C>T		intron	N/A
	CCDST	NR_186762.1		n.179+26904C>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.5244G>A	p.Ser1748Ser	synonymous	Exon 3 of 3	ENSP00000357791.3	Q86YZ3
	CCDST	ENST00000420707.5	TSL:5	n.158+26877C>T		intron	N/A
	CCDST	ENST00000593011.5	TSL:4	n.296+47965C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000111 AC: 16 AN: 144076 Hom.: 0 Cov.: 55

Gnomad AFR AF: 0.000104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000728

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000235

Gnomad FIN AF: 0.0000972

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000135

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000165 AC: 1 AN: 60516 AF XY: 0.0000330

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000724 AC: 105 AN: 1451256 Hom.: 0 Cov.: 112 AF XY: 0.0000706 AC XY: 51 AN XY: 722208

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

African (AFR) AF: 0.0000302 AC: 1 AN: 33076

American (AMR) AF: 0.0000225 AC: 1 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25960

East Asian (EAS) AF: 0.00 AC: 0 AN: 39518

South Asian (SAS) AF: 0.000140 AC: 12 AN: 85506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

Middle Eastern (MID) AF: 0.000183 AC: 1 AN: 5464

European-Non Finnish (NFE) AF: 0.0000788 AC: 87 AN: 1104128

Other (OTH) AF: 0.0000501 AC: 3 AN: 59908

⚠️ 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: 0.000118 AC: 17 AN: 144170 Hom.: 0 Cov.: 55 AF XY: 0.000157 AC XY: 11 AN XY: 70080

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

African (AFR) AF: 0.000130 AC: 5 AN: 38556

American (AMR) AF: 0.0000728 AC: 1 AN: 13738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3310

East Asian (EAS) AF: 0.00 AC: 0 AN: 4212

South Asian (SAS) AF: 0.000236 AC: 1 AN: 4240

European-Finnish (FIN) AF: 0.0000972 AC: 1 AN: 10292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.000135 AC: 9 AN: 66722

Other (OTH) AF: 0.00 AC: 0 AN: 1970

⚠️ 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: 0.00 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	5.9
DANN	Benign	0.58
PhyloP100		-3.1
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: rs201735593; hg19: chr1-152188861; COSMIC: COSV64261059;