chr5-141577472-T-A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_005219.5(DIAPH1):​c.1280+3A>T variant causes a splice region, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

DIAPH1
NM_005219.5 splice_region, intron

Scores

2
Splicing: ADA: 0.9864
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.97

Publications

0 publications found
Variant links:
Genes affected
DIAPH1 (HGNC:2876): (diaphanous related formin 1) This gene is a homolog of the Drosophila diaphanous gene, and has been linked to autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive low-frequency hearing loss. Actin polymerization involves proteins known to interact with diaphanous protein in Drosophila and mouse. It has therefore been speculated that this gene may have a role in the regulation of actin polymerization in hair cells of the inner ear. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
DIAPH1 Gene-Disease associations (from GenCC):
  • DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • autosomal dominant nonsyndromic hearing loss 1
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
  • progressive microcephaly-seizures-cortical blindness-developmental delay syndrome
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DIAPH1NM_005219.5 linkc.1280+3A>T splice_region_variant, intron_variant Intron 12 of 27 ENST00000389054.8 NP_005210.3 O60610-1Q6URC4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DIAPH1ENST00000389054.8 linkc.1280+3A>T splice_region_variant, intron_variant Intron 12 of 27 5 NM_005219.5 ENSP00000373706.4 O60610-1
DIAPH1ENST00000518047.5 linkc.1253+3A>T splice_region_variant, intron_variant Intron 11 of 26 5 ENSP00000428268.2 O60610-3
DIAPH1ENST00000647433.1 linkc.1280+3A>T splice_region_variant, intron_variant Intron 12 of 28 ENSP00000494675.1 A0A2R8Y5N1
DIAPH1ENST00000523100.5 linkn.*510A>T downstream_gene_variant 5 ENSP00000428208.1 B4E2I7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.20
CADD
Benign
11
DANN
Benign
0.94
PhyloP100
2.0

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.86
SpliceAI score (max)
0.85
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.85
Position offset: 3

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

Publications

Other links and lift over

dbSNP: rs747583916; hg19: chr5-140957039; API