19-54360051-G-A

Variant names:

• chr19-54360051-G-A
• rs1335407056
• NM_002287.6:c.386C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002287.6(LAIR1):​c.386C>T​(p.Ser129Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 15)
  • Exomes 𝑓: 0.000094 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LAIR1 NM_002287.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0240
• Publications: 0 publications found

Genes affected

LAIR1 (HGNC:6477): (leukocyte associated immunoglobulin like receptor 1) The protein encoded by this gene is an inhibitory receptor found on peripheral mononuclear cells, including natural killer cells, T cells, and B cells. Inhibitory receptors regulate the immune response to prevent lysis of cells recognized as self. The gene is a member of both the immunoglobulin superfamily and the leukocyte-associated inhibitory receptor family. The gene maps to a region of 19q13.4 called the leukocyte receptor cluster, which contains at least 29 genes encoding leukocyte-expressed receptors of the immunoglobulin superfamily. The encoded protein has been identified as an anchor for tyrosine phosphatase SHP-1, and may induce cell death in myeloid leukemias. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09764543).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002287.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAIR1	NM_002287.6	MANE Select	c.386C>T	p.Ser129Phe	missense	Exon 4 of 10	NP_002278.2	Q6GTX8-1
	LAIR1	NM_001289025.3		c.383C>T	p.Ser128Phe	missense	Exon 4 of 10	NP_001275954.2	D3YTC8
	LAIR1	NM_001289026.3		c.365C>T	p.Ser122Phe	missense	Exon 4 of 10	NP_001275955.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAIR1	ENST00000391742.7	TSL:1 MANE Select	c.386C>T	p.Ser129Phe	missense	Exon 4 of 10	ENSP00000375622.2	Q6GTX8-1
	LAIR1	ENST00000348231.8	TSL:1	c.364+865C>T		intron	N/A	ENSP00000301193.4	Q6GTX8-2
	LAIR1	ENST00000474878.5	TSL:1	c.361+865C>T		intron	N/A	ENSP00000418998.1	Q6GTX8-3

Frequencies

GnomAD3 genomes AF: 0.000412 AC: 49 AN: 118854 Hom.: 0 Cov.: 15

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000714

Gnomad OTH AF: 0.000649

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000944 AC: 40 AN: 423524 Hom.: 0 Cov.: 5 AF XY: 0.000110 AC XY: 24 AN XY: 218048

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000937 AC: 13 AN: 13878

American (AMR) AF: 0.00 AC: 0 AN: 17910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12090

East Asian (EAS) AF: 0.00 AC: 0 AN: 26182

South Asian (SAS) AF: 0.00 AC: 0 AN: 29158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23642

Middle Eastern (MID) AF: 0.000564 AC: 1 AN: 1774

European-Non Finnish (NFE) AF: 0.0000871 AC: 24 AN: 275584

Other (OTH) AF: 0.0000858 AC: 2 AN: 23306

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000162098), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000412 AC: 49 AN: 118936 Hom.: 0 Cov.: 15 AF XY: 0.000431 AC XY: 24 AN XY: 55684

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00133 AC: 44 AN: 33148

American (AMR) AF: 0.00 AC: 0 AN: 11394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3054

East Asian (EAS) AF: 0.00 AC: 0 AN: 3324

South Asian (SAS) AF: 0.00 AC: 0 AN: 2956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0000714 AC: 4 AN: 56034

Other (OTH) AF: 0.000645 AC: 1 AN: 1550

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000000222045), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000169 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	4.7
DANN	Benign	0.39
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.94	T
PhyloP100		0.024
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.022
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.98	D
Vest4		0.20
MutPred		0.25		Loss of phosphorylation at S129 (P = 0.0096)
MVP		0.24
MPC		2.1
ClinPred		0.14	T
GERP RS		0.80
gMVP		0.11
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1335407056; hg19: chr19-54871658; COSMIC: COSV57306713; COSMIC: COSV57306713;