NM_021246.4:c.64A>T

Variant names:

• chr6-31715510-A-T
• rs759293818
• NM_021246.4:c.64A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021246.4(LY6G6D):​c.64A>T​(p.Met22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LY6G6D NM_021246.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.288
• Publications: 0 publications found

Genes affected

LY6G6D (HGNC:13935): (lymphocyte antigen 6 family member G6D) LY6G6D belongs to a cluster of leukocyte antigen-6 (LY6) genes located in the major histocompatibility complex (MHC) class III region on chromosome 6. Members of the LY6 superfamily typically contain 70 to 80 amino acids, including 8 to 10 cysteines. Most LY6 proteins are attached to the cell surface by a glycosylphosphatidylinositol (GPI) anchor that is directly involved in signal transduction (Mallya et al., 2002 [PubMed 12079290]).[supplied by OMIM, Apr 2009]

LY6G6F-LY6G6D (HGNC:38821): (LY6G6F-LY6G6D readthrough) This locus represents naturally occurring readthrough transcription between the neighboring LY6G6F (lymphocyte antigen 6 family member G6F) and LY6G6D (lymphocyte antigen 6 family member G6D) genes on chromosome 6. The readthrough transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Jul 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.072779745).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021246.4. 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
	LY6G6D	NM_021246.4	MANE Select	c.64A>T	p.Met22Leu	missense	Exon 2 of 3	NP_067069.2	A0A1L6Z9X4
	LY6G6F-LY6G6D	NM_001353334.2		c.811A>T	p.Met271Leu	missense	Exon 5 of 6	NP_001340263.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LY6G6D	ENST00000375825.8	TSL:1 MANE Select	c.64A>T	p.Met22Leu	missense	Exon 2 of 3	ENSP00000364985.3	O95868
	LY6G6F-LY6G6D	ENST00000503322.1	TSL:1	c.811A>T	p.Met271Leu	missense	Exon 5 of 6	ENSP00000421232.1
	LY6G6D	ENST00000375824.1	TSL:1	c.64A>T	p.Met22Leu	missense	Exon 2 of 3	ENSP00000364984.1	F6XWZ1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152086 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246490 AF XY: 0.00

Gnomad AFR exome AF: 0.0000662

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460482 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726510

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111788

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152086 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74278

African (AFR) AF: 0.000169 AC: 7 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.00000847 AC: 1

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	0.18
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	10
DANN	Benign	0.86
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.057	N
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.29
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.075
Sift	Benign	0.28	T
Sift4G	Benign	0.089	T
Polyphen		0.24	B
Vest4		0.25
MutPred		0.27		Loss of catalytic residue at M22 (P = 8e-04)
MVP		0.14
MPC		0.13
ClinPred		0.060	T
GERP RS		4.0
PromoterAI		0.0018	Neutral
Varity_R		0.26
gMVP		0.29
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs759293818; hg19: chr6-31683287;