NM_005219.5:c.1851_1853dupTCC

Variant names:

• chr5-141573996-T-TGGA
• rs3075570
• NM_005219.5:c.1851_1853dupTCC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_005219.5(DIAPH1):​c.1851_1853dupTCC​(p.Pro618dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 1,510,582 control chromosomes in the GnomAD database, including 343 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P618P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.046 (162 hom., cov: 28)
  • Exomes 𝑓: 0.030 (181 hom.)
• Consequence: DIAPH1 NM_005219.5 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.13
• Publications: 2 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)

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005219.5
• BP6: Variant 5-141573996-T-TGGA is Benign according to our data. Variant chr5-141573996-T-TGGA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.088 is higher than 0.05.

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.1851_1853dupTCC	p.Pro618dup	disruptive_inframe_insertion	Exon 16 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.1824_1826dupTCC	p.Pro609dup	disruptive_inframe_insertion	Exon 15 of 27	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.1851_1853dupTCC	p.Pro618dup	disruptive_inframe_insertion	Exon 16 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.1851_1853dupTCC	p.Pro618dup	disruptive_inframe_insertion	Exon 16 of 28	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000518047.5	TSL:5	c.1824_1826dupTCC	p.Pro609dup	disruptive_inframe_insertion	Exon 15 of 27	ENSP00000428268.2	O60610-3
	DIAPH1	ENST00000647433.1		c.1851_1853dupTCC	p.Pro618dup	disruptive_inframe_insertion	Exon 16 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes AF: 0.0457 AC: 5727 AN: 125396 Hom.: 162 Cov.: 28

Gnomad AFR AF: 0.0908

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.0300

Gnomad ASJ AF: 0.0526

Gnomad EAS AF: 0.0290

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.00618

Gnomad MID AF: 0.0310

Gnomad NFE AF: 0.0311

Gnomad OTH AF: 0.0369

GnomAD2 exomes AF: 0.0450 AC: 3773 AN: 83800 AF XY: 0.0457

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.0433

Gnomad ASJ exome AF: 0.0676

Gnomad EAS exome AF: 0.0539

Gnomad FIN exome AF: 0.00691

Gnomad NFE exome AF: 0.0407

Gnomad OTH exome AF: 0.0536

GnomAD4 exome AF: 0.0299 AC: 41374 AN: 1385114 Hom.: 181 Cov.: 35 AF XY: 0.0296 AC XY: 20243 AN XY: 683052

African (AFR) AF: 0.0799 AC: 2506 AN: 31376

American (AMR) AF: 0.0248 AC: 876 AN: 35300

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 1154 AN: 24720

East Asian (EAS) AF: 0.0279 AC: 983 AN: 35294

South Asian (SAS) AF: 0.0243 AC: 1891 AN: 77766

European-Finnish (FIN) AF: 0.00671 AC: 318 AN: 47412

Middle Eastern (MID) AF: 0.0331 AC: 147 AN: 4442

European-Non Finnish (NFE) AF: 0.0294 AC: 31498 AN: 1071408

Other (OTH) AF: 0.0349 AC: 2001 AN: 57396

GnomAD4 genome AF: 0.0457 AC: 5733 AN: 125468 Hom.: 162 Cov.: 28 AF XY: 0.0447 AC XY: 2693 AN XY: 60188

African (AFR) AF: 0.0907 AC: 2993 AN: 32994

American (AMR) AF: 0.0300 AC: 373 AN: 12432

Ashkenazi Jewish (ASJ) AF: 0.0526 AC: 162 AN: 3078

East Asian (EAS) AF: 0.0291 AC: 126 AN: 4336

South Asian (SAS) AF: 0.0205 AC: 77 AN: 3764

European-Finnish (FIN) AF: 0.00618 AC: 48 AN: 7762

Middle Eastern (MID) AF: 0.0288 AC: 6 AN: 208

European-Non Finnish (NFE) AF: 0.0311 AC: 1816 AN: 58400

Other (OTH) AF: 0.0384 AC: 65 AN: 1692

Alfa AF: 0.0151 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=76/24	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3075570; hg19: chr5-140953563; COSMIC: COSV53878469; COSMIC: COSV53878469;