chr11-17509813-G-T

Variant names:

• chr11-17509813-G-T
• NM_153676.4:c.1556C>A

Variant summary

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

The NM_153676.4(USH1C):​c.1556C>A​(p.Pro519Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 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. P519S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.771

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]

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=0.15175581).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4	c.1556C>A	p.Pro519Gln	missense_variant	Exon 18 of 27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.1284+7588C>A		intron_variant	Intron 15 of 20	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.1556C>A	p.Pro519Gln	missense_variant	Exon 18 of 27	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.1284+7588C>A		intron_variant	Intron 15 of 20	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444886 Hom.: 0 Cov.: 38 AF XY: 0.00000139 AC XY: 1 AN XY: 718818

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.67
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.74
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.47	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.060
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0060	D
Vest4		0.38
MutPred		0.18		Loss of glycosylation at P519 (P = 6e-04);
MVP		0.31
MPC		0.082
ClinPred		0.43	T
GERP RS		1.8
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-17531360;