2-74530427-G-T

Variant names:

• chr2-74530427-G-T
• rs72470544
• NM_013247.5:c.421G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_013247.5(HTRA2):​c.421G>T​(p.Ala141Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0234 in 1,603,176 control chromosomes in the GnomAD database, including 485 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A141A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (25 hom., cov: 33)
  • Exomes 𝑓: 0.024 (460 hom.)
• Consequence: HTRA2 NM_013247.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: -0.725
• Publications: 42 publications found

Genes affected

HTRA2 (HGNC:14348): (HtrA serine peptidase 2) This gene encodes a serine protease. The protein has been localized in the endoplasmic reticulum and interacts with an alternatively spliced form of mitogen-activated protein kinase 14. The protein has also been localized to the mitochondria with release to the cytosol following apoptotic stimulus. The protein is thought to induce apoptosis by binding the apoptosis inhibitory protein baculoviral IAP repeat-containing 4. Nuclear localization of this protein has also been observed. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

HTRA2 Gene-Disease associations (from GenCC):

• 3-methylglutaconic aciduria type 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020277798).
• BP6: Variant 2-74530427-G-T is Benign according to our data. Variant chr2-74530427-G-T is described in ClinVar as Benign. ClinVar VariationId is 4342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0171 (2602/152342) while in subpopulation NFE AF = 0.0261 (1777/68030). AF 95% confidence interval is 0.0251. There are 25 homozygotes in GnomAd4. There are 1273 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013247.5. 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
	HTRA2	NM_013247.5	MANE Select	c.421G>T	p.Ala141Ser	missense	Exon 1 of 8	NP_037379.1	O43464-1
	HTRA2	NM_001321727.1		c.421G>T	p.Ala141Ser	missense	Exon 1 of 7	NP_001308656.1	O43464-3
	HTRA2	NM_001321728.1		c.421G>T	p.Ala141Ser	missense	Exon 1 of 7	NP_001308657.1	A0A8Q3SIX7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA2	ENST00000258080.8	TSL:1 MANE Select	c.421G>T	p.Ala141Ser	missense	Exon 1 of 8	ENSP00000258080.3	O43464-1
	HTRA2	ENST00000437202.2	TSL:1	c.421G>T	p.Ala141Ser	missense	Exon 1 of 7	ENSP00000399166.2	O43464-3
	HTRA2	ENST00000352222.7	TSL:1	c.421G>T	p.Ala141Ser	missense	Exon 1 of 6	ENSP00000312893.3	O43464-2

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2600 AN: 152224 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.00499

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0253

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0261

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0191 AC: 4404 AN: 230376 AF XY: 0.0200

Gnomad AFR exome AF: 0.00377

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0151

Gnomad EAS exome AF: 0.0000574

Gnomad FIN exome AF: 0.0283

Gnomad NFE exome AF: 0.0266

Gnomad OTH exome AF: 0.0204

GnomAD4 exome AF: 0.0241 AC: 34943 AN: 1450834 Hom.: 460 Cov.: 33 AF XY: 0.0240 AC XY: 17360 AN XY: 721836

African (AFR) AF: 0.00314 AC: 105 AN: 33404

American (AMR) AF: 0.0106 AC: 473 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 416 AN: 26064

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39568

South Asian (SAS) AF: 0.0188 AC: 1614 AN: 85974

European-Finnish (FIN) AF: 0.0271 AC: 1214 AN: 44840

Middle Eastern (MID) AF: 0.0354 AC: 204 AN: 5764

European-Non Finnish (NFE) AF: 0.0266 AC: 29543 AN: 1110608

Other (OTH) AF: 0.0228 AC: 1372 AN: 60170

GnomAD4 genome AF: 0.0171 AC: 2602 AN: 152342 Hom.: 25 Cov.: 33 AF XY: 0.0171 AC XY: 1273 AN XY: 74480

African (AFR) AF: 0.00498 AC: 207 AN: 41588

American (AMR) AF: 0.0119 AC: 182 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4832

European-Finnish (FIN) AF: 0.0253 AC: 269 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0261 AC: 1777 AN: 68030

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.0159 Hom.: 5

Bravo AF: 0.0161

TwinsUK AF: 0.0283 AC: 105

ALSPAC AF: 0.0231 AC: 89

ESP6500AA AF: 0.00398 AC: 17

ESP6500EA AF: 0.0255 AC: 214

ExAC AF: 0.0196 AC: 2363

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Parkinson disease 13, autosomal dominant, susceptibility to (2)
-	-	2	Parkinson disease 13, autosomal dominant, susceptibility to;C4310650:3-methylglutaconic aciduria type 8 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.82
DANN	Benign	0.89
DEOGEN2	Benign	0.052	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.72
PrimateAI	Benign	0.46	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.015
Sift	Benign	0.81	T
Sift4G	Benign	0.91	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.82
ClinPred		0.00062	T
GERP RS		-1.0
PromoterAI		0.065	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.33
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs72470544; hg19: chr2-74757554; COSMIC: COSV51207131; COSMIC: COSV51207131;