Variant 8-132076124-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001145095.3(HHLA1):c.1246C>T(p.Leu416Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000258 in 1,550,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HHLA1
NM_001145095.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.364

Variant links:

Genes affected

HHLA1 (HGNC:4904): (HHLA1 neighbor of OC90) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

HHLA1 links:

ENSG00000258417 (HGNC:):

ENSG00000258417 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05980146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HHLA1	NM_001145095.3 linkuse as main transcript	c.1246C>T	p.Leu416Phe	missense_variant	14/17	ENST00000414222.2	NP_001138567.1	C9JL84-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HHLA1	ENST00000414222.2 linkuse as main transcript	c.1246C>T	p.Leu416Phe	missense_variant	14/17	5	NM_001145095.3	ENSP00000388322.1	C9JL84-1
ENSG00000258417	ENST00000262283.5 linkuse as main transcript	c.472C>T	p.Leu158Phe	missense_variant	4/18	5		ENSP00000262283.5	I6L893
HHLA1	ENST00000473291.1 linkuse as main transcript	n.1708C>T		non_coding_transcript_exon_variant	4/7	1
HHLA1	ENST00000673615.1 linkuse as main transcript	c.1354C>T	p.Leu452Phe	missense_variant	15/18			ENSP00000500443.1	A0A5F9ZHM0

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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

AF:

0.00000143

AC:

AN:

1398192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689676

show subpopulations

Gnomad4 AFR exome

AF:

0.0000633

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2022

The c.1246C>T (p.L416F) alteration is located in exon 13 (coding exon 13) of the HHLA1 gene. This alteration results from a C to T substitution at nucleotide position 1246, causing the leucine (L) at amino acid position 416 to be replaced by a phenylalanine (F). 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

0.079

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

2.0

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0068

.;T;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.62

T;T;T

M_CAP

Benign

0.036

MetaRNN

Benign

0.060

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

.;L;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.99

N;N;N

REVEL

Benign

0.029

Sift

Uncertain

0.010

D;T;T

Sift4G

Benign

0.070

T;T;T

Polyphen

0.81

.;P;.

Vest4

0.17

MutPred

0.18

.;Gain of catalytic residue at L416 (P = 0.0302);.;

MVP

0.11

ClinPred

0.34

GERP RS

0.0035

Varity_R

0.060

gMVP

0.047

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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