chr22-37303370-A-G

Variant names:

• chr22-37303370-A-G
• rs1929263596
• NM_013385.5:c.664A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_013385.5(CYTH4):​c.664A>G​(p.Asn222Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYTH4 NM_013385.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0600

Genes affected

CYTH4 (HGNC:9505): (cytohesin 4) This gene encodes a member of the PSCD family of proteins, which have an N-terminal coiled-coil motif, a central Sec7 domain, and a C-terminal pleckstrin homology (PH) domain. The coiled-coil motif is involved in homodimerization, the Sec7 domain contains guanine-nucleotide exchange protein (GEP) activity, and the PH domain interacts with phospholipids and is responsible for association of PSCDs with membranes. Members of this family function as GEPs for ADP-ribosylation factors (ARFs), which are guanine nucleotide-binding proteins involved in vesicular trafficking pathways. This protein exhibits GEP activity in vitro with ARF1 and ARF5, but is inactive with ARF6. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06554979).
• BP6: Variant 22-37303370-A-G is Benign according to our data. Variant chr22-37303370-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2537810.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYTH4	NM_013385.5	c.664A>G	p.Asn222Asp	missense_variant	Exon 8 of 13	ENST00000248901.11	NP_037517.1
CYTH4	NM_001318024.2	c.493A>G	p.Asn165Asp	missense_variant	Exon 8 of 13		NP_001304953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYTH4	ENST00000248901.11	c.664A>G	p.Asn222Asp	missense_variant	Exon 8 of 13	1	NM_013385.5	ENSP00000248901.6
CYTH4	ENST00000462927.5	n.709A>G		non_coding_transcript_exon_variant	Exon 8 of 13	2
CYTH4	ENST00000447919.1	n.*75A>G		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Apr 18, 2023

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	Benign	0.053
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.7
DANN	Benign	0.93
DEOGEN2	Benign	0.0083	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.015	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.040
Sift	Benign	0.66	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.042
MutPred		0.46		Gain of phosphorylation at S224 (P = 0.0977);
MVP		0.40
MPC		0.44
ClinPred		0.043	T
GERP RS		-0.14
Varity_R		0.079
gMVP		0.42

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: rs1929263596; hg19: chr22-37699411;