Genetic Variant CHRFAM7A:p.Gly84Arg (chr15-30373056-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_139320.2(CHRFAM7A):c.250G>A(p.Gly84Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000071 ( 0 hom., cov: 22)

Exomes 𝑓: 0.000028 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

CHRFAM7A
NM_139320.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.79

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]

CHRFAM7A links:

LOC105370751 (HGNC:):

LOC105370751 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25166234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRFAM7A	NM_139320.2 link	c.250G>A	p.Gly84Arg	missense_variant	Exon 6 of 10	ENST00000299847.7	NP_647536.1	Q494W8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRFAM7A	ENST00000299847.7 link	c.250G>A	p.Gly84Arg	missense_variant	Exon 6 of 10	1	NM_139320.2	ENSP00000299847.3		Q494W8

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

141178

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000254

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

GnomAD3 exomes

AF:

0.0000816

AC:

AN:

232902

Hom.:

AF XY:

0.0000239

AC XY:

AN XY:

125676

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000395

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000121

Gnomad SAS exome

AF:

0.0000365

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000281

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000277

AC:

AN:

1445516

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

719394

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000431

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000127

Gnomad4 SAS exome

AF:

0.0000234

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000728

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000708

AC:

AN:

141178

Hom.:

Cov.:

AF XY:

0.0000147

AC XY:

AN XY:

68236

show subpopulations

Gnomad4 AFR

AF:

0.0000254

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

Alfa

AF:

0.0000481

Hom.:

ExAC

AF:

0.0000582

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.250G>A (p.G84R) alteration is located in exon 6 (coding exon 4) of the CHRFAM7A gene. This alteration results from a G to A substitution at nucleotide position 250, causing the glycine (G) at amino acid position 84 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

0.71

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

0.075

Eigen_PC

Benign

-0.084

FATHMM_MKL

Benign

0.14

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.25

T;T

MetaSVM

Uncertain

-0.053

MutationAssessor

Uncertain

2.2

M;.

PROVEAN

Uncertain

-2.5

D;D

REVEL

Uncertain

0.55

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.017

D;.

Polyphen

0.98

D;.

Vest4

0.69

MutPred

0.57

Gain of MoRF binding (P = 0.014);Gain of MoRF binding (P = 0.014);

MVP

0.68

ClinPred

0.24

GERP RS

2.1

Varity_R

0.38

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over