1-158255260-G-A

Variant summary

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

The NM_001763.3(CD1A):c.235G>A(p.Glu79Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000884 in 1,614,058 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (1 hom.)
• Consequence: CD1A NM_001763.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.629

Genes affected

CD1A (HGNC:1634): (CD1a molecule) This gene encodes a member of the CD1 family of transmembrane glycoproteins, which are structurally related to the major histocompatibility complex (MHC) proteins and form heterodimers with beta-2-microglobulin. The CD1 proteins mediate the presentation of primarily lipid and glycolipid antigens of self or microbial origin to T cells. The human genome contains five CD1 family genes organized in a cluster on chromosome 1. The CD1 family members are thought to differ in their cellular localization and specificity for particular lipid ligands. The protein encoded by this gene localizes to the plasma membrane and to recycling vesicles of the early endocytic system. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

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=0.18494391).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD1A	NM_001763.3	c.235G>A	p.Glu79Lys	missense_variant	2/6	ENST00000289429.6
CD1A	NM_001320652.2	c.202G>A	p.Glu68Lys	missense_variant	2/6
CD1A	XM_024450738.2	c.-234G>A		5_prime_UTR_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD1A	ENST00000289429.6	c.235G>A	p.Glu79Lys	missense_variant	2/6	1	NM_001763.3	P1

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000955

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000501 AC: 126 AN: 251404 Hom.: 0 AF XY: 0.000545 AC XY: 74 AN XY: 135870

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000941

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000918 AC: 1342 AN: 1461880 Hom.: 1 Cov.: 33 AF XY: 0.000873 AC XY: 635 AN XY: 727242

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00115

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.000559 AC: 85 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74340

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000955

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000918 Hom.: 1

Bravo AF: 0.000654

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000527 AC: 64

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00124

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

Sep 01, 2021

The c.235G>A (p.E79K) alteration is located in exon 2 (coding exon 2) of the CD1A gene. This alteration results from a G to A substitution at nucleotide position 235, causing the glutamic acid (E) at amino acid position 79 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	0.20
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.029
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.056	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.089
Sift	Benign	0.031	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.92	P
Vest4		0.44
MVP		0.58
MPC		0.28
ClinPred		0.063	T
GERP RS		4.5
Varity_R		0.68
gMVP		0.39

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: rs148007865; hg19: chr1-158225050;