17-74920102-G-A

Position:

chr17-74920102-G-A

Variant summary

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

The NM_173477.5(USH1G):c.734C>T(p.Ser245Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 1,603,564 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

USH1G
NM_173477.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.91

Variant links:

Genes affected

USH1G (HGNC:16356): (USH1 protein network component sans) This gene encodes a protein that contains three ankyrin domains, a class I PDZ-binding motif and a sterile alpha motif. The encoded protein interacts with harmonin, which is associated with Usher syndrome type 1C. This protein plays a role in the development and maintenance of the auditory and visual systems and functions in the cohesion of hair bundles formed by inner ear sensory cells. Mutations in this gene are associated with Usher syndrome type 1G (USH1G). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

USH1G links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1G	NM_173477.5 linkuse as main transcript	c.734C>T	p.Ser245Leu	missense_variant	2/3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3 linkuse as main transcript	c.425C>T	p.Ser142Leu	missense_variant	2/3		NP_001269418.1	Q495M9B4DL95
USH1G	XM_011524296.2 linkuse as main transcript	c.425C>T	p.Ser142Leu	missense_variant	2/3		XP_011522598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
USH1G	ENST00000614341.5 linkuse as main transcript	c.734C>T	p.Ser245Leu	missense_variant	2/3	1	NM_173477.5	ENSP00000480279.1	Q495M9
USH1G	ENST00000579243.1 linkuse as main transcript	n.*333C>T		non_coding_transcript_exon_variant	2/3	2		ENSP00000462568.1	J3KSN5
USH1G	ENST00000579243.1 linkuse as main transcript	n.*333C>T		3_prime_UTR_variant	2/3	2		ENSP00000462568.1	J3KSN5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

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:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1451310

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722388

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 17, 2011

The Ser245Leu variant in USH1G has not been reported in the literature nor previ ously identified by our laboratory. This residue is conserved across species and computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest that the Ser245Leu variant may impact the protein. However, this information is not predictive enou gh to assume pathogenicity. It should be noted that this lab has only sequenced the USH1G in 16 Asian individuals and no Asian healthy controls. In addition, he althy control information is unavailable from either public databases or scienti fic literature, such that the full spectrum of benign variation has not yet been defined for this population. Future analysis could reveal that the Ser245Leu va riant is common in this population and therefore unlikely to be pathogenic. In s ummary, the clinical significance of this variant cannot be determined with cert ainty at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.036

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.2

PrimateAI

Pathogenic

0.81

Sift4G

Benign

0.13

Polyphen

0.97

Vest4

0.77

MutPred

0.44

Loss of phosphorylation at S245 (P = 0.0168);

MVP

0.50

ClinPred

0.97

GERP RS

3.7

Varity_R

0.35

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over