chr15-30372170-T-C

Variant names:

• chr15-30372170-T-C
• rs769409282
• NM_139320.2:c.500A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_139320.2(CHRFAM7A):​c.500A>G​(p.Asp167Gly) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., cov: 8)
  • Exomes 𝑓: 0.000021 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRFAM7A NM_139320.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.40
• 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 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

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.500A>G	p.Asp167Gly	missense	Exon 7 of 10	NP_647536.1	Q494W8
	CHRFAM7A	NM_148911.1		c.227A>G	p.Asp76Gly	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.500A>G	p.Asp167Gly	missense	Exon 7 of 10	ENSP00000299847.3	Q494W8
	CHRFAM7A	ENST00000401522.7	TSL:1	c.227A>G	p.Asp76Gly	missense	Exon 8 of 11	ENSP00000385389.3	A0A0A6YYA8
	CHRFAM7A	ENST00000853243.1		c.500A>G	p.Asp167Gly	missense	Exon 8 of 11	ENSP00000523302.1

Frequencies

GnomAD3 genomes AF: 0.0000449 AC: 3 AN: 66828 Hom.: 0 Cov.: 8

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000863

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: 0.0000939 AC: 14 AN: 149040 AF XY: 0.0000871

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000868

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000206 AC: 21 AN: 1017890 Hom.: 1 Cov.: 16 AF XY: 0.0000175 AC XY: 9 AN XY: 513094

African (AFR) AF: 0.00 AC: 0 AN: 19956

American (AMR) AF: 0.00 AC: 0 AN: 37372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17940

East Asian (EAS) AF: 0.000529 AC: 20 AN: 37824

South Asian (SAS) AF: 0.00 AC: 0 AN: 70436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3614

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 745426

Other (OTH) AF: 0.0000232 AC: 1 AN: 43130

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000449 AC: 3 AN: 66828 Hom.: 0 Cov.: 8 AF XY: 0.0000643 AC XY: 2 AN XY: 31108

African (AFR) AF: 0.00 AC: 0 AN: 13504

American (AMR) AF: 0.00 AC: 0 AN: 6338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1654

East Asian (EAS) AF: 0.000863 AC: 3 AN: 3478

South Asian (SAS) AF: 0.00 AC: 0 AN: 2204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 162

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 34632

Other (OTH) AF: 0.00 AC: 0 AN: 862

Alfa AF: 0.0000843 Hom.: 0

ExAC AF: 0.0000615 AC: 6

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	0.83
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.4
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.79		Loss of stability (P = 0.0523)
MVP		0.65
ClinPred		0.82	D
GERP RS		2.6
Varity_R		0.76
gMVP		0.75
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs769409282; hg19: chr15-30664373;