rs1464543932

Variant names:

• chr15-30362774-A-C
• rs1464543932
• NM_139320.2:c.758T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_139320.2(CHRFAM7A):​c.758T>G​(p.Leu253Arg) 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 0.000015 (0 hom., cov: 21)
  • Failed GnomAD Quality Control
• Consequence: CHRFAM7A NM_139320.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.59

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]

ENSG00000289455 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRFAM7A	NM_139320.2	c.758T>G	p.Leu253Arg	missense_variant	Exon 10 of 10	ENST00000299847.7	NP_647536.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRFAM7A	ENST00000299847.7	c.758T>G	p.Leu253Arg	missense_variant	Exon 10 of 10	1	NM_139320.2	ENSP00000299847.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2 AN: 130492 Hom.: 0 Cov.: 21 FAILED QC

Gnomad AFR AF: 0.0000615

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

GnomAD4 exome Cov.: 16

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000153 AC: 2 AN: 130492 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 62710

Gnomad4 AFR AF: 0.0000615

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.758T>G (p.L253R) alteration is located in exon 10 (coding exon 8) of the CHRFAM7A gene. This alteration results from a T to G substitution at nucleotide position 758, causing the leucine (L) at amino acid position 253 to be replaced by an arginine (R). 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	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;.
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	4.4	H;.;.
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.92
MutPred		0.83		Loss of ubiquitination at K256 (P = 0.0417);.;.;
MVP		0.78
ClinPred		1.0	D
GERP RS		3.1
Varity_R		0.87
gMVP		0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs1464543932; hg19: chr15-30654977;