15-30371143-C-T

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

Scores

4
11
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.30
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
CHRFAM7ANM_139320.2 linkc.565G>A p.Val189Met missense_variant Exon 8 of 10 ENST00000299847.7 NP_647536.1 Q494W8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHRFAM7AENST00000299847.7 linkc.565G>A p.Val189Met missense_variant Exon 8 of 10 1 NM_139320.2 ENSP00000299847.3 Q494W8
CHRFAM7AENST00000401522.7 linkc.292G>A p.Val98Met missense_variant Exon 9 of 11 1 ENSP00000385389.3 A0A0A6YYA8
CHRFAM7AENST00000397827.7 linkc.292G>A p.Val98Met missense_variant Exon 7 of 9 5 ENSP00000380927.3 A0A0A6YYA8
CHRFAM7AENST00000692430.1 linkn.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
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1222637529; hg19: chr15-30663346; COSMIC: COSV100241724; COSMIC: COSV100241724; API