2-159835606-G-A

Position:

• chr2-159835606-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002349.4(LY75):​c.3547C>T​(p.His1183Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,613,782 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: LY75 NM_002349.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.84

Genes affected

LY75 (HGNC:6729): (lymphocyte antigen 75) Predicted to enable signaling receptor activity. Predicted to be involved in immune response and inflammatory response. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

LY75-CD302 (HGNC:38828): (LY75-CD302 readthrough) This locus represents naturally occurring read-through transcription between the neighboring lymphocyte antigen 75 (LY75) and CD302 molecule (CD302) genes. Alternative splicing results in multiple transcript variants encoding fusion products that share sequence identity with each individual gene product. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019774228).
• BP6: Variant 2-159835606-G-A is Benign according to our data. Variant chr2-159835606-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 710587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LY75	NM_002349.4	c.3547C>T	p.His1183Tyr	missense_variant	26/35	ENST00000263636.5	NP_002340.2
LY75-CD302	NM_001198759.1	c.3547C>T	p.His1183Tyr	missense_variant	26/39		NP_001185688.1
LY75-CD302	NM_001198760.1	c.3547C>T	p.His1183Tyr	missense_variant	26/38		NP_001185689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LY75	ENST00000263636.5	c.3547C>T	p.His1183Tyr	missense_variant	26/35	1	NM_002349.4	ENSP00000263636.4
LY75-CD302	ENST00000504764.5	c.3547C>T	p.His1183Tyr	missense_variant	26/39	2		ENSP00000423463.1
LY75-CD302	ENST00000505052.1	c.3547C>T	p.His1183Tyr	missense_variant	26/38	2		ENSP00000421035.1

Frequencies

GnomAD3 genomes AF: 0.000953 AC: 145 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00111 AC: 278 AN: 250918 Hom.: 0 AF XY: 0.00103 AC XY: 140 AN XY: 135604

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00159

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00167 AC: 2437 AN: 1461472 Hom.: 3 Cov.: 31 AF XY: 0.00161 AC XY: 1174 AN XY: 727002

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00256

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00192

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.000945 AC: 144 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74476

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00169 Hom.: 1

Bravo AF: 0.00112

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000980 AC: 119

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	.;.;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.062
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;.;L
PROVEAN	Benign	-0.40	N;N;N
REVEL	Benign	0.097
Sift	Benign	0.66	T;T;T
Sift4G	Benign	0.071	T;T;T
Polyphen		0.76	.;.;P
Vest4		0.20
MVP		0.25
MPC		0.061
ClinPred		0.011	T
GERP RS		3.9
Varity_R		0.084
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs140695949; hg19: chr2-160692117;