22-37296051-A-G

Variant names:

• chr22-37296051-A-G
• rs16998061
• NM_013385.5:c.220A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013385.5(CYTH4):​c.220A>G​(p.Met74Val) variant causes a missense change. The variant allele was found at a frequency of 0.00371 in 1,613,002 control chromosomes in the GnomAD database, including 199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.020 (104 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (95 hom.)
• Consequence: CYTH4 NM_013385.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.99

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004670739).
• BP6: Variant 22-37296051-A-G is Benign according to our data. Variant chr22-37296051-A-G is described in ClinVar as [Benign]. Clinvar id is 781618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYTH4	NM_013385.5	c.220A>G	p.Met74Val	missense_variant	Exon 4 of 13	ENST00000248901.11	NP_037517.1
CYTH4	NM_001318024.2	c.49A>G	p.Met17Val	missense_variant	Exon 4 of 13		NP_001304953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYTH4	ENST00000248901.11	c.220A>G	p.Met74Val	missense_variant	Exon 4 of 13	1	NM_013385.5	ENSP00000248901.6

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3067 AN: 152168 Hom.: 104 Cov.: 33

Gnomad AFR AF: 0.0701

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0162

GnomAD3 exomes AF: 0.00501 AC: 1239 AN: 247444 Hom.: 34 AF XY: 0.00363 AC XY: 486 AN XY: 134012

Gnomad AFR exome AF: 0.0700

Gnomad AMR exome AF: 0.00323

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000985

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00200 AC: 2921 AN: 1460716 Hom.: 95 Cov.: 31 AF XY: 0.00169 AC XY: 1227 AN XY: 726548

Gnomad4 AFR exome AF: 0.0710

Gnomad4 AMR exome AF: 0.00399

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.0202 AC: 3071 AN: 152286 Hom.: 104 Cov.: 33 AF XY: 0.0194 AC XY: 1445 AN XY: 74476

Gnomad4 AFR AF: 0.0700

Gnomad4 AMR AF: 0.00752

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00415 Hom.: 40

Bravo AF: 0.0222

ESP6500AA AF: 0.0726 AC: 320

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00643 AC: 781

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 05, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T;T;T;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
MetaRNN	Benign	0.0047	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	.;M;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0030	D;T;D;D
Polyphen		0.018	.;B;.;.
Vest4		0.35, 0.35, 0.35
MVP		0.39
MPC		0.39
ClinPred		0.040	T
GERP RS		5.1
Varity_R		0.50
gMVP		0.39

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: rs16998061; hg19: chr22-37692092;