Genetic Variant HM13:c.455-842A>T (chr20-31548187-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_178581.3(HM13):c.455-842A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000185 in 541,372 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.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

HM13
NM_178581.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.278

Publications

0 publications found

Variant links:

Genes affected

HM13 (HGNC:16435): (histocompatibility minor 13) The protein encoded by this gene, which localizes to the endoplasmic reticulum, catalyzes intramembrane proteolysis of some signal peptides after they have been cleaved from a preprotein. This activity is required to generate signal sequence-derived human lymphocyte antigen-E epitopes that are recognized by the immune system, and to process hepatitis C virus core protein. The encoded protein is an integral membrane protein with sequence motifs characteristic of the presenilin-type aspartic proteases. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

HM13 links:

MCTS2 (HGNC:49760): (MCTS family member 2) This locus represents a retrogene copy of MCTS1 (GeneID:28985) and contains an ORF similar to that parent gene. This locus is situated in a differentially methylated region (DMR) and transcripts in this region are imprinted. [provided by RefSeq, Nov 2021]

MCTS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178581.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HM13	NM_178581.3	MANE Select	c.455-842A>T	intron	N/A	NP_848696.1	Q8TCT9-2
HM13	NM_178580.3		c.455-842A>T	intron	N/A	NP_848695.1	Q8TCT9-4
HM13	NM_030789.4		c.455-842A>T	intron	N/A	NP_110416.1	Q8TCT9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HM13	ENST00000398174.9	TSL:1 MANE Select	c.455-842A>T	intron	N/A	ENSP00000381237.3	Q8TCT9-2
HM13	ENST00000340852.9	TSL:1	c.455-842A>T	intron	N/A	ENSP00000343032.5	Q8TCT9-1
MCTS2	ENST00000718306.1		c.*138A>T	3_prime_UTR	Exon 1 of 9	ENSP00000520739.1	A0A3B3IRV3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000185

AC:

AN:

541372

Hom.:

AF XY:

0.00000348

AC XY:

AN XY:

287608

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

14724

American (AMR)

AF:

0.00

AC:

AN:

25442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14512

East Asian (EAS)

AF:

0.00

AC:

AN:

34664

South Asian (SAS)

AF:

0.00

AC:

AN:

53210

European-Finnish (FIN)

AF:

0.0000215

AC:

AN:

46534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3032

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

320758

Other (OTH)

AF:

0.00

AC:

AN:

28496

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

6.1

(source)

DANN

Benign

0.67

PhyloP100

0.28

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over