rs200186513

Variant names:

• chr15-30373137-T-C
• rs200186513
• NM_139320.2:c.169A>G

Variant summary

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

The NM_139320.2(CHRFAM7A):​c.169A>G​(p.Lys57Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 143,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 24)
  • Exomes 𝑓: 0.00019 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRFAM7A NM_139320.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.32

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]

LOC105370751 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031099498).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRFAM7A	NM_139320.2	c.169A>G	p.Lys57Glu	missense_variant	Exon 6 of 10	ENST00000299847.7	NP_647536.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRFAM7A	ENST00000299847.7	c.169A>G	p.Lys57Glu	missense_variant	Exon 6 of 10	1	NM_139320.2	ENSP00000299847.3

Frequencies

GnomAD3 genomes AF: 0.000251 AC: 36 AN: 143670 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000923

Gnomad ASJ AF: 0.00424

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00338

Gnomad NFE AF: 0.000123

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000383 AC: 89 AN: 232332 Hom.: 4 AF XY: 0.000383 AC XY: 48 AN XY: 125400

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.00693

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000749

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.000178

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000191 AC: 264 AN: 1380026 Hom.: 4 Cov.: 30 AF XY: 0.000187 AC XY: 129 AN XY: 688750

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000367

Gnomad4 ASJ exome AF: 0.00644

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000599

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000490

Gnomad4 OTH exome AF: 0.000452

GnomAD4 genome AF: 0.000250 AC: 36 AN: 143790 Hom.: 0 Cov.: 24 AF XY: 0.000272 AC XY: 19 AN XY: 69806

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000922

Gnomad4 ASJ AF: 0.00424

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000123

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000865 Hom.: 0

ExAC AF: 0.000340 AC: 41

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.169A>G (p.K57E) alteration is located in exon 6 (coding exon 4) of the CHRFAM7A gene. This alteration results from a A to G substitution at nucleotide position 169, causing the lysine (K) at amino acid position 57 to be replaced by a glutamic acid (E). 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	0.56
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.031	T;T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.8	M;.
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0050	D;.
Polyphen		0.76	P;.
Vest4		0.90
MutPred		0.72		Loss of ubiquitination at K57 (P = 0.0255);Loss of ubiquitination at K57 (P = 0.0255);
MVP		0.50
ClinPred		0.24	T
GERP RS		1.9
Varity_R		0.62
gMVP		0.74

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: rs200186513; hg19: chr15-30665340;