15-30371143-C-T

Variant names:

• chr15-30371143-C-T
• rs1222637529
• NM_139320.2:c.565G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_139320.2(CHRFAM7A):​c.565G>A​(p.Val189Met) 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 0.000074 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000046 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRFAM7A NM_139320.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.30

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]

LOC105370751 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRFAM7A	NM_139320.2	c.565G>A	p.Val189Met	missense_variant	Exon 8 of 10	ENST00000299847.7	NP_647536.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRFAM7A	ENST00000299847.7	c.565G>A	p.Val189Met	missense_variant	Exon 8 of 10	1	NM_139320.2	ENSP00000299847.3
CHRFAM7A	ENST00000401522.7	c.292G>A	p.Val98Met	missense_variant	Exon 9 of 11	1		ENSP00000385389.3
CHRFAM7A	ENST00000397827.7	c.292G>A	p.Val98Met	missense_variant	Exon 7 of 9	5		ENSP00000380927.3
CHRFAM7A	ENST00000692430.1	n.517G>A		non_coding_transcript_exon_variant	Exon 3 of 5

Frequencies

GnomAD3 genomes AF: 0.0000742 AC: 11 AN: 148212 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000765

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000199

Gnomad SAS AF: 0.000422

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000595

Gnomad OTH AF: 0.000494

GnomAD3 exomes AF: 0.0000217 AC: 5 AN: 230396 Hom.: 0 AF XY: 0.00000802 AC XY: 1 AN XY: 124736

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000480

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000463 AC: 65 AN: 1402812 Hom.: 0 Cov.: 27 AF XY: 0.0000414 AC XY: 29 AN XY: 700034

Gnomad4 AFR exome AF: 0.0000325

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000178

Gnomad4 SAS exome AF: 0.0000353

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000481

Gnomad4 OTH exome AF: 0.0000513

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000742 AC: 11 AN: 148212 Hom.: 0 Cov.: 24 AF XY: 0.000111 AC XY: 8 AN XY: 72294

Gnomad4 AFR AF: 0.0000765

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000199

Gnomad4 SAS AF: 0.000422

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000595

Gnomad4 OTH AF: 0.000494

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.565G>A (p.V189M) alteration is located in exon 8 (coding exon 6) of the CHRFAM7A gene. This alteration results from a G to A substitution at nucleotide position 565, causing the valine (V) at amino acid position 189 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;.
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;.
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	3.2	M;.;.
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.041	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.70		Loss of catalytic residue at V189 (P = 0.0177);.;.;
MVP		0.68
ClinPred		0.97	D
GERP RS		2.6
Varity_R		0.64
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1222637529; hg19: chr15-30663346; COSMIC: COSV100241724; COSMIC: COSV100241724;