chr7-6190463-T-C

Variant names:

• chr7-6190463-T-C
• rs1783774463
• NM_004227.4:c.103A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001367580.1(CYTH3):​c.-1075A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000243 in 1,236,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000070 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: CYTH3 NM_001367580.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.57
• Publications: 0 publications found

Genes affected

CYTH3 (HGNC:9504): (cytohesin 3) This gene encodes a member of the PSCD (pleckstrin homology, Sec7 and coiled-coil domains) family. PSCD family members have identical structural organization that consists of 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 appear to mediate the regulation of protein sorting and membrane trafficking. This encoded protein is involved in the control of Golgi structure and function, and it may have a physiological role in regulating ADP-ribosylation factor protein 6 (ARF) functions, in addition to acting on ARF1. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13251734).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367580.1. 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
	CYTH3	NM_004227.4	MANE Select	c.103A>G	p.Ile35Val	missense	Exon 2 of 13	NP_004218.1	O43739-2
	CYTH3	NM_001367580.1		c.-1075A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 13	NP_001354509.1	B7Z2V9
	CYTH3	NM_001367581.1		c.-622A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 14	NP_001354510.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYTH3	ENST00000350796.8	TSL:1 MANE Select	c.103A>G	p.Ile35Val	missense	Exon 2 of 13	ENSP00000297044.7	O43739-2
	CYTH3	ENST00000898314.1		c.241A>G	p.Ile81Val	missense	Exon 3 of 14	ENSP00000568373.1
	CYTH3	ENST00000898313.1		c.196A>G	p.Ile66Val	missense	Exon 3 of 14	ENSP00000568372.1

Frequencies

GnomAD3 genomes AF: 0.00000700 AC: 1 AN: 142774 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1093466 Hom.: 0 Cov.: 33 AF XY: 0.00000367 AC XY: 2 AN XY: 544484

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24400

American (AMR) AF: 0.00 AC: 0 AN: 24014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19322

East Asian (EAS) AF: 0.00 AC: 0 AN: 23758

South Asian (SAS) AF: 0.00 AC: 0 AN: 68740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4466

European-Non Finnish (NFE) AF: 0.00000233 AC: 2 AN: 857254

Other (OTH) AF: 0.00 AC: 0 AN: 44010

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000700 AC: 1 AN: 142774 Hom.: 0 Cov.: 28 AF XY: 0.0000145 AC XY: 1 AN XY: 69078

African (AFR) AF: 0.00 AC: 0 AN: 39582

American (AMR) AF: 0.00 AC: 0 AN: 14112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3386

East Asian (EAS) AF: 0.00 AC: 0 AN: 4088

South Asian (SAS) AF: 0.00 AC: 0 AN: 4094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65818

Other (OTH) AF: 0.00 AC: 0 AN: 1980

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.089
Sift	Benign	0.21	T
Sift4G	Benign	0.32	T
Polyphen		0.015	B
Vest4		0.26
MutPred		0.18		Gain of MoRF binding (P = 0.0972)
MVP		0.22
MPC		0.050
ClinPred		0.71	D
GERP RS		4.5
Varity_R		0.26
gMVP		0.26
Mutation Taster		=91/9	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: rs1783774463; hg19: chr7-6230094;