Genetic Variant SERHL2:p.Ala6Val (chr22-42554037-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014509.5(SERHL2):c.17C>T(p.Ala6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Consequence

SERHL2
NM_014509.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.12

Variant links:

Genes affected

SERHL2 (HGNC:29446): (serine hydrolase like 2) Predicted to enable hydrolase activity. Predicted to be located in cytoplasmic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

SERHL2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06805855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERHL2	NM_014509.5 link	c.17C>T	p.Ala6Val	missense_variant	Exon 1 of 12	ENST00000327678.10	NP_055324.2	Q9H4I8-1A0A140VK89

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERHL2	ENST00000327678.10 link	c.17C>T	p.Ala6Val	missense_variant	Exon 1 of 12	1	NM_014509.5	ENSP00000331376.5		Q9H4I8-1
SERHL2	ENST00000407614.8 link	c.17C>T	p.Ala6Val	missense_variant	Exon 1 of 7	1		ENSP00000385691.4		Q9H4I8-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.17C>T (p.A6V) alteration is located in exon 1 (coding exon 1) of the SERHL2 gene. This alteration results from a C to T substitution at nucleotide position 17, causing the alanine (A) at amino acid position 6 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.14

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0021

.;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.58

T;T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.068

T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.22

N;N;N;N

REVEL

Benign

0.013

Sift

Benign

0.30

T;T;D;D

Sift4G

Benign

0.36

T;T;D;.

Polyphen

0.18, 0.28

.;B;.;B

Vest4

0.12

MutPred

0.21

Loss of disorder (P = 0.084);Loss of disorder (P = 0.084);Loss of disorder (P = 0.084);Loss of disorder (P = 0.084);

MVP

0.030

MPC

1.1

ClinPred

0.27

GERP RS

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.030

gMVP

0.34

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over