Genetic Variant NM_139320.2:c.1196C>T (chr15-30362336-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_139320.2(CHRFAM7A):c.1196C>T(p.Ser399Leu) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0075 ( 0 hom., cov: 0)

Exomes 𝑓: 0.12 ( 54 hom. )

Failed GnomAD Quality Control

Consequence

CHRFAM7A
NM_139320.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 9.14

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.041679204).

BP6

Variant 15-30362336-G-A is Benign according to our data. Variant chr15-30362336-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2391467.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRFAM7A	NM_139320.2 link	c.1196C>T	p.Ser399Leu	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.1196C>T	p.Ser399Leu	missense_variant	Exon 10 of 10	1	NM_139320.2	ENSP00000299847.3		Q494W8

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

138

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad NFE

AF:

0.100

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.115

AC:

21723

AN:

188408

Hom.:

Cov.:

AF XY:

0.111

AC XY:

11051

AN XY:

99372

show subpopulations

Gnomad4 AFR exome

AF:

0.0251

Gnomad4 AMR exome

AF:

0.0789

Gnomad4 ASJ exome

AF:

0.139

Gnomad4 EAS exome

AF:

0.00792

Gnomad4 SAS exome

AF:

0.0758

Gnomad4 FIN exome

AF:

0.160

Gnomad4 NFE exome

AF:

0.138

Gnomad4 OTH exome

AF:

0.112

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00746

AC:

AN:

134

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

AN XY:

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.100

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0383

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 22, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.051

T;.;.

Eigen

Benign

0.075

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

D;D;.

M_CAP

Benign

0.012

MetaRNN

Benign

0.042

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.2

M;.;.

PROVEAN

Uncertain

-4.1

D;D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.023

D;D;D

Sift4G

Benign

0.063

T;T;T

Polyphen

0.22

B;.;.

Vest4

0.53

MutPred

0.54

Gain of catalytic residue at S399 (P = 0.0083);.;.;

ClinPred

0.041

GERP RS

3.3

Varity_R

0.36

gMVP

0.76

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