NM_013385.5:c.262C>T

Variant names:

• chr22-37297591-C-T
• rs73887105
• NM_013385.5:c.262C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_013385.5(CYTH4):​c.262C>T​(p.Leu88Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,613,914 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (11 hom.)
• Consequence: CYTH4 NM_013385.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.27
• Publications: 0 publications found

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]

ENSG00000298470 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 22-37297591-C-T is Benign according to our data. Variant chr22-37297591-C-T is described in ClinVar as Benign. ClinVar VariationId is 734144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.27 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.007 (1066/152296) while in subpopulation AFR AF = 0.0247 (1028/41540). AF 95% confidence interval is 0.0235. There are 11 homozygotes in GnomAd4. There are 484 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013385.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYTH4	NM_013385.5	MANE Select	c.262C>T	p.Leu88Leu	synonymous	Exon 5 of 13	NP_037517.1	Q9UIA0
	CYTH4	NM_001318024.2		c.91C>T	p.Leu31Leu	synonymous	Exon 5 of 13	NP_001304953.1	B4E2V8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYTH4	ENST00000248901.11	TSL:1 MANE Select	c.262C>T	p.Leu88Leu	synonymous	Exon 5 of 13	ENSP00000248901.6	Q9UIA0
	CYTH4	ENST00000469886.5	TSL:1	n.317C>T		non_coding_transcript_exon	Exon 5 of 5
	CYTH4	ENST00000868416.1		c.259C>T	p.Leu87Leu	synonymous	Exon 5 of 13	ENSP00000538475.1

Frequencies

GnomAD3 genomes AF: 0.00699 AC: 1064 AN: 152178 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

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: 0.0000294

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00177 AC: 446 AN: 251458 AF XY: 0.00111

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000742 AC: 1084 AN: 1461618 Hom.: 11 Cov.: 30 AF XY: 0.000644 AC XY: 468 AN XY: 727124

African (AFR) AF: 0.0278 AC: 929 AN: 33462

American (AMR) AF: 0.000895 AC: 40 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53400

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111840

Other (OTH) AF: 0.00151 AC: 91 AN: 60376

GnomAD4 genome AF: 0.00700 AC: 1066 AN: 152296 Hom.: 11 Cov.: 32 AF XY: 0.00650 AC XY: 484 AN XY: 74478

African (AFR) AF: 0.0247 AC: 1028 AN: 41540

American (AMR) AF: 0.00150 AC: 23 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00352 Hom.: 4

Bravo AF: 0.00841

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	9.3
DANN	Benign	0.85
PhyloP100		2.3
Mutation Taster		=89/11	polymorphism

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: rs73887105; hg19: chr22-37693632;