7-6190493-G-T

Variant names:

• chr7-6190493-G-T
• rs11978706
• NM_004227.4:c.73C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004227.4(CYTH3):​c.73C>A​(p.Leu25Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 144,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L25V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYTH3 NM_004227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.427
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04295069).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004227.4. 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.73C>A	p.Leu25Ile	missense	Exon 2 of 13	NP_004218.1	O43739-2
	CYTH3	NM_001367580.1		c.-1105C>A		5_prime_UTR	Exon 2 of 13	NP_001354509.1	B7Z2V9
	CYTH3	NM_001367581.1		c.-652C>A		5_prime_UTR	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.73C>A	p.Leu25Ile	missense	Exon 2 of 13	ENSP00000297044.7	O43739-2
	CYTH3	ENST00000898314.1		c.211C>A	p.Leu71Ile	missense	Exon 3 of 14	ENSP00000568373.1
	CYTH3	ENST00000898313.1		c.166C>A	p.Leu56Ile	missense	Exon 3 of 14	ENSP00000568372.1

Frequencies

GnomAD3 genomes AF: 0.0000138 AC: 2 AN: 144586 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000510

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1361212 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 671860

African (AFR) AF: 0.00 AC: 0 AN: 30102

American (AMR) AF: 0.00 AC: 0 AN: 29836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24454

East Asian (EAS) AF: 0.00 AC: 0 AN: 34798

South Asian (SAS) AF: 0.00 AC: 0 AN: 75380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5570

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1067492

Other (OTH) AF: 0.00 AC: 0 AN: 56586

GnomAD4 genome AF: 0.0000138 AC: 2 AN: 144586 Hom.: 0 Cov.: 30 AF XY: 0.0000288 AC XY: 2 AN XY: 69550

African (AFR) AF: 0.0000510 AC: 2 AN: 39204

American (AMR) AF: 0.00 AC: 0 AN: 14016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 4798

South Asian (SAS) AF: 0.00 AC: 0 AN: 4582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66964

Other (OTH) AF: 0.00 AC: 0 AN: 1986

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.5
DANN	Benign	0.84
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.43
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.029
Sift	Benign	0.22	T
Sift4G	Benign	0.20	T
Polyphen		0.12	B
Vest4		0.17
MutPred		0.20		Gain of MoRF binding (P = 0.1253)
MVP		0.16
MPC		0.061
ClinPred		0.24	T
GERP RS		-4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.070
gMVP		0.13
Mutation Taster		=96/4	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: rs11978706; hg19: chr7-6230124;