22-37300911-T-C

Variant names:

• chr22-37300911-T-C
• rs139032641
• NM_013385.5:c.439T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013385.5(CYTH4):​c.439T>C​(p.Phe147Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,614,020 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: CYTH4 NM_013385.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.95

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24251461).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYTH4	NM_013385.5	c.439T>C	p.Phe147Leu	missense_variant	Exon 7 of 13	ENST00000248901.11	NP_037517.1
CYTH4	NM_001318024.2	c.268T>C	p.Phe90Leu	missense_variant	Exon 7 of 13		NP_001304953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYTH4	ENST00000248901.11	c.439T>C	p.Phe147Leu	missense_variant	Exon 7 of 13	1	NM_013385.5	ENSP00000248901.6
CYTH4	ENST00000439667.1	n.478T>C		non_coding_transcript_exon_variant	Exon 7 of 8	3
CYTH4	ENST00000447919.1	n.30T>C		non_coding_transcript_exon_variant	Exon 1 of 3	5
CYTH4	ENST00000462927.5	n.484T>C		non_coding_transcript_exon_variant	Exon 7 of 13	2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000287 AC: 72 AN: 250570 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135528

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00269

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000274

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000197 AC: 288 AN: 1461690 Hom.: 1 Cov.: 31 AF XY: 0.000199 AC XY: 145 AN XY: 727132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00249

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000146

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000367 Hom.: 0

Bravo AF: 0.000208

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.439T>C (p.F147L) alteration is located in exon 7 (coding exon 7) of the CYTH4 gene. This alteration results from a T to C substitution at nucleotide position 439, causing the phenylalanine (F) at amino acid position 147 to be replaced by a leucine (L). 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	0.98
BayesDel_addAF	Benign	0.00027	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.046	D
Polyphen		0.78	P
Vest4		0.88
MutPred		0.83		Gain of catalytic residue at F147 (P = 0.092);
MVP		0.73
MPC		1.3
ClinPred		0.16	T
GERP RS		4.0
Varity_R		0.83
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139032641; hg19: chr22-37696952;