5-141516966-G-C

Variant names:

• chr5-141516966-G-C
• rs761387295
• NM_005219.5:c.3704C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_005219.5(DIAPH1):​c.3704C>G​(p.Ser1235Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,096 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1235L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.79
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39377087).

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.3704C>G	p.Ser1235Trp	missense	Exon 28 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.3677C>G	p.Ser1226Trp	missense	Exon 27 of 27	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.*4C>G		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.3704C>G	p.Ser1235Trp	missense	Exon 28 of 28	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000518047.5	TSL:5	c.3677C>G	p.Ser1226Trp	missense	Exon 27 of 27	ENSP00000428268.2	O60610-3
	DIAPH1	ENST00000468119.3	TSL:4	c.110C>G	p.Ser37Trp	missense	Exon 3 of 3	ENSP00000493546.1	H7C2W8

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249524 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461876 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74364

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.8	L
PhyloP100		1.8
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.37		Loss of disorder (P = 1e-04)
MVP		0.93
MPC		1.7
ClinPred		0.81	D
GERP RS		5.1
Varity_R		0.16
gMVP		0.57
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs761387295; hg19: chr5-140896533;