chr5-141577472-T-A

Variant names:

• chr5-141577472-T-A
• rs747583916
• NM_005219.5:c.1280+3A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

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: Splicing: ADA: 0.9864
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.97
• Publications: 0 publications found

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

ACMG classification

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
DIAPH1	NM_005219.5	c.1280+3A>T		splice_region_variant, intron_variant	Intron 12 of 27	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.1280+3A>T		splice_region_variant, intron_variant	Intron 12 of 27	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5	c.1253+3A>T		splice_region_variant, intron_variant	Intron 11 of 26	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1	c.1280+3A>T		splice_region_variant, intron_variant	Intron 12 of 28			ENSP00000494675.1
DIAPH1	ENST00000523100.5	n.*510A>T		downstream_gene_variant		5		ENSP00000428208.1

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

Other links and lift over

dbSNP: rs747583916; hg19: chr5-140957039;