7-35873685-A-G

Variant names:

• chr7-35873685-A-G
• rs1786298349
• NM_001788.6:c.422A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001788.6(SEPTIN7):​c.422A>G​(p.Tyr141Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SEPTIN7 NM_001788.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

Genes affected

SEPTIN7 (HGNC:1717): (septin 7) This gene encodes a protein that is highly similar to the CDC10 protein of Saccharomyces cerevisiae. The protein also shares similarity with Diff 6 of Drosophila and with H5 of mouse. Each of these similar proteins, including the yeast CDC10, contains a GTP-binding motif. The yeast CDC10 protein is a structural component of the 10 nm filament which lies inside the cytoplasmic membrane and is essential for cytokinesis. This human protein functions in gliomagenesis and in the suppression of glioma cell growth, and it is required for the association of centromere-associated protein E with the kinetochore. Alternative splicing results in multiple transcript variants. Several related pseudogenes have been identified on chromosomes 5, 7, 9, 10, 11, 14, 17 and 19. [provided by RefSeq, Jul 2011]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPTIN7	NM_001788.6	c.422A>G	p.Tyr141Cys	missense_variant	Exon 6 of 14	ENST00000350320.11	NP_001779.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPTIN7	ENST00000350320.11	c.422A>G	p.Tyr141Cys	missense_variant	Exon 6 of 14	5	NM_001788.6	ENSP00000344868.8
SEPTIN7	ENST00000635047.1	c.263A>G	p.Tyr88Cys	missense_variant	Exon 6 of 7	4		ENSP00000489480.1
SEPTIN7	ENST00000635175.1	n.*339A>G		non_coding_transcript_exon_variant	Exon 6 of 14	2		ENSP00000489192.1
SEPTIN7	ENST00000635175.1	n.*339A>G		3_prime_UTR_variant	Exon 6 of 14	2		ENSP00000489192.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.422A>G (p.Y141C) alteration is located in exon 6 (coding exon 6) of the SEPT7 gene. This alteration results from a A to G substitution at nucleotide position 422, causing the tyrosine (Y) at amino acid position 141 to be replaced by a cysteine (C). 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	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	.;T;T;T;.;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Benign	-0.29	T
PhyloP100		9.3
PrimateAI	Pathogenic	0.93	D
REVEL	Pathogenic	0.75
Sift4G	Uncertain	0.022	D;D;D;D;D;D
Vest4		0.85
MutPred		0.84		.;Gain of catalytic residue at L142 (P = 0.0171);.;.;.;.;
MVP		0.82
MPC		1.6
ClinPred		1.0	D
GERP RS		5.1
gMVP		0.89
Mutation Taster		=11/89	disease causing

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

Other links and lift over

dbSNP: rs1786298349; hg19: chr7-35913295;