rs116342492

Variant names:

• chr5-141515487-A-G
• rs116342492
• NM_005219.5:c.*1364T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005219.5(DIAPH1):​c.*1364T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 152,302 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (20 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DIAPH1 NM_005219.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.276
• Publications: 1 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: Orphanet, ClinGen
• progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant nonsyndromic hearing loss 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000301000 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-141515487-A-G is Benign according to our data. Variant chr5-141515487-A-G is described in ClinVar as Benign. ClinVar VariationId is 351264.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1633/152302) while in subpopulation AFR AF = 0.0289 (1200/41556). AF 95% confidence interval is 0.0275. There are 20 homozygotes in GnomAd4. There are 805 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005219.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	NM_005219.5	MANE Select	c.*1364T>C		3_prime_UTR	Exon 28 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.*1364T>C		3_prime_UTR	Exon 27 of 27	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.*1483T>C		3_prime_UTR	Exon 29 of 29	NP_001300936.1	A0A2R8Y5N1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	ENST00000389054.8	TSL:5 MANE Select	c.*1364T>C		3_prime_UTR	Exon 28 of 28	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000647433.1		c.*1483T>C		3_prime_UTR	Exon 29 of 29	ENSP00000494675.1	A0A2R8Y5N1
	DIAPH1	ENST00000448451.6	TSL:2	c.*1364T>C		3_prime_UTR	Exon 3 of 3	ENSP00000408159.2	H7C2W8

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1633 AN: 152184 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00370

Gnomad OTH AF: 0.0105

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 30 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 20

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 22

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.0107 AC: 1633 AN: 152302 Hom.: 20 Cov.: 33 AF XY: 0.0108 AC XY: 805 AN XY: 74482

African (AFR) AF: 0.0289 AC: 1200 AN: 41556

American (AMR) AF: 0.00660 AC: 101 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4824

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10618

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00370 AC: 252 AN: 68030

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.00792 Hom.: 4

Bravo AF: 0.0119

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant nonsyndromic hearing loss 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.0
DANN	Benign	0.63
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs116342492; hg19: chr5-140895054;