NM_153676.4:c.225T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_153676.4(USH1C):c.225T>C(p.Asp75Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.00326 in 1,613,964 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 21 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 119 hom. )

Consequence

USH1C
NM_153676.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.12

Publications

5 publications found

Variant links:

Genes affected

USH1C (HGNC:12597): (USH1 protein network component harmonin) This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

USH1C Gene-Disease associations (from GenCC):

Usher syndrome type 1C
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, G2P
Usher syndrome type 1
Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
autosomal recessive nonsyndromic hearing loss 18A
Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

USH1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 11-17531422-A-G is Benign according to our data. Variant chr11-17531422-A-G is described in ClinVar as Benign. ClinVar VariationId is 47996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0682 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153676.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USH1C	NM_153676.4	MANE Select	c.225T>C	p.Asp75Asp	synonymous	Exon 3 of 27	NP_710142.1	Q9Y6N9-5
USH1C	NM_005709.4	MANE Plus Clinical	c.225T>C	p.Asp75Asp	synonymous	Exon 3 of 21	NP_005700.2	A0A0S2Z4U9
USH1C	NM_001440679.1		c.258T>C	p.Asp86Asp	synonymous	Exon 3 of 22	NP_001427608.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USH1C	ENST00000005226.12	TSL:5 MANE Select	c.225T>C	p.Asp75Asp	synonymous	Exon 3 of 27	ENSP00000005226.7	Q9Y6N9-5
USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.225T>C	p.Asp75Asp	synonymous	Exon 3 of 21	ENSP00000317018.4	Q9Y6N9-1
USH1C	ENST00000527020.5	TSL:1	c.225T>C	p.Asp75Asp	synonymous	Exon 3 of 20	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes

AF:

0.00520

AC:

791

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0220

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.0547

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00796

AC:

1998

AN:

250944

AF XY:

0.00699

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.0185

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.0581

Gnomad FIN exome

AF:

0.00977

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00539

GnomAD4 exome

AF:

0.00306

AC:

4470

AN:

1461732

Hom.:

119

Cov.:

AF XY:

0.00294

AC XY:

2139

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.0189

AC:

847

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

AN:

26134

East Asian (EAS)

AF:

0.0703

AC:

2792

AN:

39690

South Asian (SAS)

AF:

0.000847

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00863

AC:

461

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0000513

AC:

AN:

1111950

Other (OTH)

AF:

0.00379

AC:

229

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

296

591

887

1182

1478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00520

AC:

792

AN:

152232

Hom.:

Cov.:

AF XY:

0.00638

AC XY:

475

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41558

American (AMR)

AF:

0.0220

AC:

336

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.0552

AC:

285

AN:

5164

South Asian (SAS)

AF:

0.000416

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0118

AC:

125

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68010

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000954

Hom.:

Bravo

AF:

0.00591

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Usher syndrome type 1C (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

9.8

(source)

DANN

Benign

0.72

PhyloP100

4.1

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over