chr4-8270150-C-T

Variant names:

• chr4-8270150-C-T
• rs1052955394
• NM_053044.5:c.182C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_053044.5(HTRA3):​c.182C>T​(p.Pro61Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000648 in 1,543,022 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: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: HTRA3 NM_053044.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.30
• Publications: 0 publications found

Genes affected

HTRA3 (HGNC:30406): (HtrA serine peptidase 3) Enables endopeptidase activity; identical protein binding activity; and serine-type peptidase activity. Involved in proteolysis. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000298837 (HGNC:58728):

LOC105374373 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13200921).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053044.5. 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
	HTRA3	NM_053044.5	MANE Select	c.182C>T	p.Pro61Leu	missense	Exon 1 of 9	NP_444272.1	P83110-1
	HTRA3	NM_001297559.3		c.182C>T	p.Pro61Leu	missense	Exon 1 of 7	NP_001284488.1	P83110-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA3	ENST00000307358.7	TSL:1 MANE Select	c.182C>T	p.Pro61Leu	missense	Exon 1 of 9	ENSP00000303766.2	P83110-1
	HTRA3	ENST00000382512.3	TSL:1	c.182C>T	p.Pro61Leu	missense	Exon 1 of 7	ENSP00000371952.3	P83110-2
	HTRA3	ENST00000968934.1		c.182C>T	p.Pro61Leu	missense	Exon 1 of 9	ENSP00000638993.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000632 AC: 1 AN: 158244 AF XY: 0.0000110

Gnomad AFR exome AF: 0.000154

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000503 AC: 7 AN: 1390838 Hom.: 0 Cov.: 31 AF XY: 0.00000723 AC XY: 5 AN XY: 691306

African (AFR) AF: 0.000175 AC: 5 AN: 28544

American (AMR) AF: 0.00 AC: 0 AN: 36566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24448

East Asian (EAS) AF: 0.00 AC: 0 AN: 33286

South Asian (SAS) AF: 0.00 AC: 0 AN: 80170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4524

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1089480

Other (OTH) AF: 0.00 AC: 0 AN: 57618

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

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

African (AFR) AF: 0.0000724 AC: 3 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000343967), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		5.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.069
Sift	Benign	0.27	T
Sift4G	Benign	0.45	T
Polyphen		0.21	B
Vest4		0.13
MutPred		0.28		Loss of catalytic residue at P61 (P = 0.356)
MVP		0.41
MPC		0.98
ClinPred		0.41	T
GERP RS		3.2
PromoterAI		-0.015	Neutral
Varity_R		0.25
gMVP		0.51
Mutation Taster		=65/35	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: rs1052955394; hg19: chr4-8271877;