15-30372208-G-C

Variant names:

• chr15-30372208-G-C
• rs764283527
• NM_139320.2:c.462C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_139320.2(CHRFAM7A):​c.462C>G​(p.Ile154Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000024 (1 hom., cov: 10)
  • Exomes 𝑓: 0.000036 (13 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRFAM7A NM_139320.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38
• Publications: 0 publications found

Genes affected

CHRFAM7A (HGNC:15781): (CHRNA7 (exons 5-10) and FAM7A (exons A-E) fusion) The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The family member CHRNA7, which is located on chromosome 15 in a region associated with several neuropsychiatric disorders, is partially duplicated and forms a hybrid with a novel gene from the family with sequence similarity 7 (FAM7A). Alternative splicing has been observed, and two variants exist, for this hybrid gene. The N-terminally truncated products predicted by the largest open reading frames for each variant would lack the majority of the neurotransmitter-gated ion-channel ligand binding domain but retain the transmembrane region that forms the ion channel. Although current evidence supports transcription of this hybrid gene, translation of the nicotinic acetylcholine receptor-like protein-encoding open reading frames has not been confirmed. [provided by RefSeq, Jul 2008]

LINC02249 (HGNC:32351): (long intergenic non-protein coding RNA 2249)

LOC105370751 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139320.2. 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
	CHRFAM7A	NM_139320.2	MANE Select	c.462C>G	p.Ile154Met	missense	Exon 7 of 10	NP_647536.1	Q494W8
	CHRFAM7A	NM_148911.1		c.189C>G	p.Ile63Met	missense	Exon 6 of 9	NP_683709.1	P36544

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRFAM7A	ENST00000299847.7	TSL:1 MANE Select	c.462C>G	p.Ile154Met	missense	Exon 7 of 10	ENSP00000299847.3	Q494W8
	CHRFAM7A	ENST00000401522.7	TSL:1	c.189C>G	p.Ile63Met	missense	Exon 8 of 11	ENSP00000385389.3	A0A0A6YYA8
	CHRFAM7A	ENST00000853243.1		c.462C>G	p.Ile154Met	missense	Exon 8 of 11	ENSP00000523302.1

Frequencies

GnomAD3 genomes AF: 0.0000236 AC: 2 AN: 84616 Hom.: 1 Cov.: 10

Gnomad AFR AF: 0.00

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: 0.0000471

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000426 AC: 7 AN: 164326 AF XY: 0.0000227

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000136

Gnomad NFE exome AF: 0.0000690

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000363 AC: 40 AN: 1101142 Hom.: 13 Cov.: 20 AF XY: 0.0000399 AC XY: 22 AN XY: 551976

African (AFR) AF: 0.00 AC: 0 AN: 21498

American (AMR) AF: 0.00 AC: 0 AN: 37324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18612

East Asian (EAS) AF: 0.00 AC: 0 AN: 38274

South Asian (SAS) AF: 0.00 AC: 0 AN: 72038

European-Finnish (FIN) AF: 0.0000704 AC: 3 AN: 42596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4210

European-Non Finnish (NFE) AF: 0.0000451 AC: 37 AN: 820450

Other (OTH) AF: 0.00 AC: 0 AN: 46140

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000236 AC: 2 AN: 84616 Hom.: 1 Cov.: 10 AF XY: 0.00 AC XY: 0 AN XY: 40170

African (AFR) AF: 0.00 AC: 0 AN: 17880

American (AMR) AF: 0.00 AC: 0 AN: 8230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2026

East Asian (EAS) AF: 0.00 AC: 0 AN: 4142

South Asian (SAS) AF: 0.00 AC: 0 AN: 2858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 196

European-Non Finnish (NFE) AF: 0.0000471 AC: 2 AN: 42506

Other (OTH) AF: 0.00 AC: 0 AN: 1108

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000401 AC: 4

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	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	0.097
Eigen_PC	Benign	-0.047
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		1.4
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.62
Sift	Benign	0.060	T
Sift4G	Benign	0.14	T
Polyphen		0.87	P
Vest4		0.89
MutPred		0.83		Loss of catalytic residue at L159 (P = 0.1068)
MVP		0.59
ClinPred		0.84	D
GERP RS		1.6
Varity_R		0.22
gMVP		0.77
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

dbSNP: rs764283527; hg19: chr15-30664411;