Genetic Variant CHRFAM7A:p.Glu362Lys (chr15-30362448-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_139320.2(CHRFAM7A):c.1084G>A(p.Glu362Lys) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0029 ( 0 hom., cov: 1)

Exomes 𝑓: 0.0055 ( 3 hom. )

Failed GnomAD Quality Control

Consequence

CHRFAM7A
NM_139320.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.40

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:

ENSG00000289455 (HGNC:):

ENSG00000289455 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007879078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRFAM7A	NM_139320.2 link	c.1084G>A	p.Glu362Lys	missense_variant	Exon 10 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.1084G>A	p.Glu362Lys	missense_variant	Exon 10 of 10	1	NM_139320.2	ENSP00000299847.3		Q494W8

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

2786

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00588

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00465

AC:

183

AN:

39376

Hom.:

AF XY:

0.00518

AC XY:

106

AN XY:

20480

show subpopulations

Gnomad AFR exome

AF:

0.000250

Gnomad AMR exome

AF:

0.00482

Gnomad ASJ exome

AF:

0.00649

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00673

Gnomad FIN exome

AF:

0.00199

Gnomad NFE exome

AF:

0.00618

Gnomad OTH exome

AF:

0.0110

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00548

AC:

2112

AN:

385196

Hom.:

Cov.:

AF XY:

0.00573

AC XY:

1156

AN XY:

201614

show subpopulations

Gnomad4 AFR exome

AF:

0.000447

Gnomad4 AMR exome

AF:

0.00588

Gnomad4 ASJ exome

AF:

0.00963

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00835

Gnomad4 FIN exome

AF:

0.00108

Gnomad4 NFE exome

AF:

0.00598

Gnomad4 OTH exome

AF:

0.00593

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00286

AC:

AN:

2794

Hom.:

Cov.:

AF XY:

0.00232

AC XY:

AN XY:

1294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00625

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0107

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00110

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1084G>A (p.E362K) alteration is located in exon 10 (coding exon 8) of the CHRFAM7A gene. This alteration results from a G to A substitution at nucleotide position 1084, causing the glutamic acid (E) at amino acid position 362 to be replaced by a lysine (K). 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

Benign

0.12

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;.;.

Eigen

Benign

-0.053

Eigen_PC

Benign

-0.047

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.95

D;D;.

M_CAP

Benign

0.0048

MetaRNN

Benign

0.0079

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.;.

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Benign

0.16

Sift

Benign

0.23

T;T;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.66

P;.;.

Vest4

0.32

MutPred

0.53

Gain of ubiquitination at E362 (P = 0.0114);.;.;

MVP

0.14

ClinPred

0.032

GERP RS

2.2

Varity_R

0.19

gMVP

0.62

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

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