rs1346309649

Positions:

• chr5-141588259-C-G
• chr5-141588259-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_005219.5(DIAPH1):​c.118-9G>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: DIAPH1 NM_005219.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002186
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.236

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 5-141588259-C-G is Benign according to our data. Variant chr5-141588259-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1146625.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.118-9G>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000389054.8	NP_005210.3
DIAPH1	NM_001079812.3	c.118-1062G>C		intron_variant			NP_001073280.1
DIAPH1	NM_001314007.2	c.118-9G>C		splice_polypyrimidine_tract_variant, intron_variant			NP_001300936.1
DIAPH1	XM_047416885.1	c.52-9G>C		splice_polypyrimidine_tract_variant, intron_variant			XP_047272841.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.118-9G>C		splice_polypyrimidine_tract_variant, intron_variant		5	NM_005219.5	ENSP00000373706	A2
DIAPH1	ENST00000518047.5	c.118-1062G>C		intron_variant		5		ENSP00000428268	P4
DIAPH1	ENST00000647433.1	c.118-9G>C		splice_polypyrimidine_tract_variant, intron_variant				ENSP00000494675	A2
DIAPH1	ENST00000523100.5	c.118-9G>C		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5		ENSP00000428208

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151782 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151782 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74128

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.56
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0
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

LitVar

Other links and lift over

dbSNP: rs1346309649; hg19: chr5-140967826;