8-132079771-G-A

Position:

• chr8-132079771-G-A

Variant summary

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

The NM_001145095.3(HHLA1):​c.872C>T​(p.Pro291Leu) 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. 14/18 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HHLA1 NM_001145095.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.11

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=0.06811124).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HHLA1	NM_001145095.3	c.872C>T	p.Pro291Leu	missense_variant	11/17	ENST00000414222.2	NP_001138567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HHLA1	ENST00000414222.2	c.872C>T	p.Pro291Leu	missense_variant	11/17	5	NM_001145095.3	ENSP00000388322.1
ENSG00000258417	ENST00000262283.5	c.152-1800C>T		intron_variant		5		ENSP00000262283.5
HHLA1	ENST00000473291.1	n.1334C>T		non_coding_transcript_exon_variant	1/7	1
HHLA1	ENST00000673615.1	c.980C>T	p.Pro327Leu	missense_variant	12/18			ENSP00000500443.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1399338 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690166

Gnomad4 AFR exome AF: 0.00

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 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

May 29, 2024

The c.872C>T (p.P291L) alteration is located in exon 10 (coding exon 10) of the HHLA1 gene. This alteration results from a C to T substitution at nucleotide position 872, causing the proline (P) at amino acid position 291 to be replaced by a leucine (L). 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	0.083
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.073
DANN	Benign	0.54
DEOGEN2	Benign	0.018	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.2	N;D
REVEL	Benign	0.040
Sift	Benign	0.057	T;D
Sift4G	Benign	0.55	T;T
Polyphen		0.0	B;.
Vest4		0.073
MutPred		0.41		Gain of helix (P = 6e-04);.;
MVP		0.10
ClinPred		0.045	T
GERP RS		-6.7
Varity_R		0.020
gMVP		0.13

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-133092018; COSMIC: COSV104573084;