1-215674713-C-T

Variant names:

• chr1-215674713-C-T
• NM_206933.4:c.13198G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_206933.4(USH2A):​c.13198G>A​(p.Ala4400Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4400S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58

Genes affected

USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a domain Fibronectin type-III 29 (size 87) in uniprot entity USH2A_HUMAN there are 40 pathogenic changes around while only 4 benign (91%) in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13707966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.13198G>A	p.Ala4400Thr	missense_variant	Exon 63 of 72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.13198G>A	p.Ala4400Thr	missense_variant	Exon 63 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.13198G>A	p.Ala4400Thr	missense_variant	Exon 63 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.13198G>A (p.A4400T) alteration is located in exon 63 (coding exon 62) of the USH2A gene. This alteration results from a G to A substitution at nucleotide position 13198, causing the alanine (A) at amino acid position 4400 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	15
DANN	Benign	0.51
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.50	T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.71	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.060
Sift	Benign	0.30	T
Sift4G	Benign	0.21	T
Polyphen		0.0090	B
Vest4		0.046
MutPred		0.41		Gain of loop (P = 0.1069);
MVP		0.77
MPC		0.034
ClinPred		0.078	T
GERP RS		3.9
Varity_R		0.080
gMVP		0.18

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-215848055;