8-132076091-C-T

Position:

• chr8-132076091-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145095.3(HHLA1):​c.1279G>A​(p.Glu427Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict 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)
• Consequence: HHLA1 NM_001145095.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.543

Genes affected

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

ENSG00000258417 (HGNC:):

ACMG classification

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=0.14197299).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HHLA1	NM_001145095.3	c.1279G>A	p.Glu427Lys	missense_variant	14/17	ENST00000414222.2	NP_001138567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HHLA1	ENST00000414222.2	c.1279G>A	p.Glu427Lys	missense_variant	14/17	5	NM_001145095.3	ENSP00000388322.1
ENSG00000258417	ENST00000262283.5	c.505G>A	p.Glu169Lys	missense_variant	4/18	5		ENSP00000262283.5
HHLA1	ENST00000473291.1	n.1741G>A		non_coding_transcript_exon_variant	4/7	1
HHLA1	ENST00000673615.1	c.1387G>A	p.Glu463Lys	missense_variant	15/18			ENSP00000500443.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2024

The c.1279G>A (p.E427K) alteration is located in exon 13 (coding exon 13) of the HHLA1 gene. This alteration results from a G to A substitution at nucleotide position 1279, causing the glutamic acid (E) at amino acid position 427 to be replaced by a lysine (K). 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	0.080
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	.;T;.
Eigen	Benign	-0.037
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.65	T;T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;L;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.35	N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.013	D;T;T
Sift4G	Uncertain	0.018	D;T;D
Polyphen		1.0	.;D;.
Vest4		0.26
MutPred		0.28		.;Gain of ubiquitination at E427 (P = 0.0117);.;
MVP		0.14
ClinPred		0.39	T
GERP RS		4.1
Varity_R		0.14
gMVP		0.30

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

Other links and lift over

dbSNP: rs1272560604; hg19: chr8-133088338;