8-132076096-C-G

Position:

• chr8-132076096-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001145095.3(HHLA1):​c.1274G>C​(p.Gly425Ala) 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. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HHLA1 NM_001145095.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.165

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 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=0.046405256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HHLA1	NM_001145095.3	c.1274G>C	p.Gly425Ala	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.1274G>C	p.Gly425Ala	missense_variant	14/17	5	NM_001145095.3	ENSP00000388322.1
ENSG00000258417	ENST00000262283.5	c.500G>C	p.Gly167Ala	missense_variant	4/18	5		ENSP00000262283.5
HHLA1	ENST00000473291.1	n.1736G>C		non_coding_transcript_exon_variant	4/7	1
HHLA1	ENST00000673615.1	c.1382G>C	p.Gly461Ala	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

Jun 04, 2024

The c.1274G>C (p.G425A) alteration is located in exon 13 (coding exon 13) of the HHLA1 gene. This alteration results from a G to C substitution at nucleotide position 1274, causing the glycine (G) at amino acid position 425 to be replaced by an alanine (A). 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	0.085
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.70
DANN	Benign	0.96
DEOGEN2	Benign	0.0095	.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.42	T;T;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.046	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;L;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.38	N;N;N
REVEL	Benign	0.016
Sift	Uncertain	0.0030	D;T;T
Sift4G	Uncertain	0.010	D;T;T
Polyphen		0.0	.;B;.
Vest4		0.092
MutPred		0.20		.;Loss of loop (P = 0.0153);.;
MVP		0.048
ClinPred		0.051	T
GERP RS		0.19
Varity_R		0.048
gMVP		0.11

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-133088343;